@article {695, title = {Therapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Jun 24}, pages = {1395-400}, abstract = {

BACKGROUND: Recommendations to treat older adults with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for the primary prevention of coronary heart disease events are supported by a single clinical trial restricted to adults 73 years or younger with low levels of high-density lipoprotein cholesterol.

METHODS: We investigated the association of statin use with incident cardiovascular disease and all-cause mortality during up to 7.3 years{\textquoteright} follow-up of 1250 women and 664 men from the Cardiovascular Health Study. Study participants were 65 years and older and free of cardiovascular disease at baseline. They received drug therapy to lower cholesterol levels at baseline or no treatment with a recommendation for therapy according to the National Cholesterol Education Program guidelines. Use of these drugs was assessed annually. We used proportional-hazards models to calculate hazard ratios (HRs) and 95\% confidence intervals (CIs), adjusted for confounding variables.

RESULTS: We found 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes, and 64 deaths due to coronary heart disease) and 362 total deaths from June 1, 1989, to May 31, 1997. Compared with no use of drugs to lower cholesterol levels, statin use was associated with decreased risk of cardiovascular events (multivariate HR, 0.44; 95\% CI, 0.27-0.71) and all-cause mortality (HR, 0.56; 95\% CI, 0.36-0.88). Similar associations were observed among participants 74 years or older at baseline.

CONCLUSIONS: Use of statins was associated with decreased risk of incident cardiovascular events among elderly adults. These findings lend support to the National Cholesterol Education Program guidelines, which recommend therapy for the lowering of cholesterol levels for older adults with hypercholesterolemia.

}, keywords = {Aged, Cholesterol, LDL, Coronary Disease, Female, Follow-Up Studies, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypolipidemic Agents, Incidence, Male, Multivariate Analysis, Proportional Hazards Models, Risk Factors, United States}, issn = {0003-9926}, doi = {10.1001/archinte.162.12.1395}, author = {Lemaitre, Rozenn N and Psaty, Bruce M and Heckbert, Susan R and Kronmal, Richard A and Newman, Anne B and Burke, Gregory L} } @article {730, title = {Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Mar 18}, pages = {1372-7}, abstract = {

BACKGROUND: Few studies have examined associations of fish consumption with ischemic heart disease (IHD) risk among older adults or how different types of fish meals relate to IHD risk.

METHODS AND RESULTS: In a population-based prospective cohort study, usual fish consumption was ascertained at baseline among 3910 adults aged > or =65 years and free of known cardiovascular disease in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. Over 9.3 years{\textquoteright} mean follow-up, there were 247 IHD deaths (including 148 arrhythmic deaths) and 363 incident nonfatal myocardial infarctions (MIs). After adjustment for potential confounders, consumption of tuna or other broiled or baked fish was associated with lower risk of total IHD death (P for trend=0.001) and arrhythmic IHD death (P=0.001) but not nonfatal MI (P=0.44), with 49\% lower risk of total IHD death and 58\% lower risk of arrhythmic IHD death among persons consuming tuna/other fish 3 or more times per week compared with less than once per month. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of total IHD death, arrhythmic IHD death, or nonfatal MI but rather with trends toward higher risk.

CONCLUSIONS: Among adults aged > or =65 years, modest consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower risk of IHD death, especially arrhythmic IHD death. Cardiac benefits of fish consumption may vary depending on the type of fish meal consumed.

}, keywords = {Aged, Animals, Arrhythmias, Cardiac, Diet, Eating, Fatty Acids, Omega-3, Female, Fishes, Humans, Male, Myocardial Infarction, Myocardial Ischemia, Prospective Studies, Risk, Tuna}, issn = {1524-4539}, doi = {10.1161/01.cir.0000055315.79177.16}, author = {Mozaffarian, Dariush and Lemaitre, Rozenn N and Kuller, Lewis H and Burke, Gregory L and Tracy, Russell P and Siscovick, David S} } @article {731, title = {Cereal, fruit, and vegetable fiber intake and the risk of cardiovascular disease in elderly individuals.}, journal = {JAMA}, volume = {289}, year = {2003}, month = {2003 Apr 02}, pages = {1659-66}, abstract = {

CONTEXT: People older than 65 years are the fastest-growing segment of the population and account for the majority of cardiovascular disease (CVD) morbidity, mortality, and health care expenditures. Additionally, the influence of dietary habits on risk may be less pronounced in elderly persons, when atherosclerosis is more advanced. However, few data address the influence of diet on CVD risk in this population.

OBJECTIVE: To determine whether fiber consumption from fruit, vegetable, and cereal sources (including whole grains and bran) is associated with incident CVD in elderly persons.

DESIGN: Prospective cohort study conducted from 1989 to June 2000.

SETTING AND PARTICIPANTS: Population-based, multicenter study among 3588 men and women aged 65 years or older and free of known CVD at baseline in 1989-1990. Usual dietary fiber consumption was assessed at baseline (mean participant age, 72 years) using a 99-item food frequency questionnaire.

MAIN OUTCOME MEASURE: Incident CVD (combined stroke, ischemic heart disease death, and nonfatal myocardial infarction).

RESULTS: During 8.6 years mean follow-up, there were 811 incident CVD events. After adjustment for age, sex, education, diabetes, ever smoking, pack-years of smoking, daily physical activity, exercise intensity, alcohol intake, and fruit and vegetable fiber consumption, cereal fiber consumption was inversely associated with incident CVD (P for trend =.02), with 21\% lower risk (hazard ratio [HR], 0.79; 95\% confidence interval [CI], 0.62-0.99) in the highest quintile of intake, compared with the lowest quintile. In similar analyses, neither fruit fiber intake (P for trend =.98) nor vegetable fiber intake (P for trend =.95) were associated with incident CVD. When CVD events were separately evaluated, higher cereal fiber intake was associated with lower risk of total stroke and ischemic stroke and a trend toward lower risk of ischemic heart disease death. In a post hoc analysis, dark breads such as wheat, rye, or pumpernickel were associated with a lower risk of incident CVD (HR, 0.76; 95\% CI, 0.64-0.90) rather than cereal fiber from other sources.

CONCLUSIONS: Cereal fiber consumption late in life is associated with lower risk of incident CVD, supporting recommendations for elderly individuals to increase consumption of dietary cereal fiber.

}, keywords = {Aged, Cardiovascular Diseases, Dietary Fiber, Edible Grain, Female, Fruit, Humans, Male, Nutrition Assessment, Prospective Studies, Risk, Vegetables}, issn = {0098-7484}, doi = {10.1001/jama.289.13.1659}, author = {Mozaffarian, Dariush and Kumanyika, Shiriki K and Lemaitre, Rozenn N and Olson, Jean L and Burke, Gregory L and Siscovick, David S} } @article {740, title = {Hormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study.}, journal = {J Womens Health (Larchmt)}, volume = {12}, year = {2003}, month = {2003 May}, pages = {341-50}, abstract = {

BACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF.

METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223).

RESULTS: At baseline, 62\% were never users, 26\% were past users, and 12\% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95\% confidence interval [95\% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction).

CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Estrogen Replacement Therapy, Female, Heart Failure, Humans, Incidence, Life Style, Middle Aged, Multivariate Analysis, Obesity, Osteoporosis, Postmenopausal, Proportional Hazards Models, Prospective Studies, Risk, Risk Factors, United States, Women{\textquoteright}s Health}, issn = {1540-9996}, doi = {10.1089/154099903765448853}, author = {Rea, Thomas D and Psaty, Bruce M and Heckbert, Susan R and Cushman, Mary and Meilahn, Elaine and Olson, Jean L and Lemaitre, Rozenn N and Smith, Nicholas L and Sotoodehnia, Nona and Chaves, Paulo H M} } @article {722, title = {n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {77}, year = {2003}, month = {2003 Feb}, pages = {319-25}, abstract = {

BACKGROUND: Little is known about the relation of the dietary intake of n-3 polyunsaturated fatty acids, ie, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fatty fish and alpha-linolenic acid from vegetable oils, with ischemic heart disease among older adults.

OBJECTIVE: We investigated the associations of plasma phospholipid concentrations of DHA, EPA, and alpha-linolenic acid as biomarkers of intake with the risk of incident fatal ischemic heart disease and incident nonfatal myocardial infarction in older adults.

DESIGN: We conducted a case-control study nested in the Cardiovascular Health Study, a cohort study of adults aged > or = 65 y. Cases experienced incident fatal myocardial infarction and other ischemic heart disease death (n = 54) and incident nonfatal myocardial infarction (n = 125). Matched controls were randomly selected (n = 179). We measured plasma phospholipid concentrations of n-3 polyunsaturated fatty acids in blood samples drawn approximately 2 y before the event.

RESULTS: A higher concentration of combined DHA and EPA was associated with a lower risk of fatal ischemic heart disease, and a higher concentration of alpha-linolenic acid with a tendency to lower risk, after adjustment for risk factors [odds ratio: 0.32 (95\% CI: 0.13, 0.78; P = 0.01) and 0.52 (0.24, 1.15; P = 0.1), respectively]. In contrast, n-3 polyunsaturated fatty acids were not associated with nonfatal myocardial infarction.

CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults. The association of n-3 polyunsaturated fatty acids with fatal ischemic heart disease, but not with nonfatal myocardial infarction, is consistent with possible antiarrhythmic effects of these fatty acids.

}, keywords = {Aged, alpha-Linolenic Acid, Biomarkers, Case-Control Studies, Cohort Studies, Coronary Disease, Dietary Supplements, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Female, Fish Oils, Humans, Incidence, Male, Myocardial Infarction, Odds Ratio, Phospholipids, Prevalence, Prospective Studies, Risk Factors}, issn = {0002-9165}, doi = {10.1093/ajcn/77.2.319}, author = {Lemaitre, Rozenn N and King, Irena B and Mozaffarian, Dariush and Kuller, Lewis H and Tracy, Russell P and Siscovick, David S} } @article {797, title = {Fish intake and risk of incident atrial fibrillation.}, journal = {Circulation}, volume = {110}, year = {2004}, month = {2004 Jul 27}, pages = {368-73}, abstract = {

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated.

METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years{\textquoteright} follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28\% lower risk with intake 1 to 4 times per week (HR=0.72, 95\% CI=0.58 to 0.91, P=0.005), and 31\% lower risk with intake > or =5 times per week (HR=0.69, 95\% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.

CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.

}, keywords = {Aged, Animals, Atrial Fibrillation, Cardiotonic Agents, Cohort Studies, Cooking, Diet, Dietary Fats, Fatty Acids, Omega-3, Fish Oils, Fishes, Follow-Up Studies, Humans, Incidence, Massachusetts, Proportional Hazards Models, Prospective Studies, Risk, Seafood, Tuna}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000138154.00779.A5}, author = {Mozaffarian, Dariush and Psaty, Bruce M and Rimm, Eric B and Lemaitre, Rozenn N and Burke, Gregory L and Lyles, Mary F and Lefkowitz, David and Siscovick, David S} } @article {818, title = {Fish consumption and stroke risk in elderly individuals: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Jan 24}, pages = {200-6}, abstract = {

BACKGROUND: Associations between fish consumption and stroke risk have been inconsistent, possibly because of the differences in types of fish meals consumed. Additionally, such relationships have not been specifically evaluated in the elderly, in whom disease burden may be high and diet less influential.

METHODS: Among 4775 adults 65 years or older (range, 65-98 years) and free of known cerebrovascular disease at baseline in 1989-1990, usual dietary intake was assessed using a food frequency questionnaire. In a subset, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain n-3 fatty acid levels. Incident strokes were prospectively ascertained.

RESULTS: During 12 years of follow-up, participants experienced 626 incident strokes, including 529 ischemic strokes. In multivariate analyses, tuna/other fish consumption was inversely associated with total stroke (P = .04) and ischemic stroke (P = .02), with 27\% lower risk of ischemic stroke with an intake of 1 to 4 times per week (hazard ratio [HR], 0.73; 95\% confidence interval [CI], 0.55-0.98) and 30\% lower risk with intake of 5 or more times per week (HR, 0.70; 95\% CI, 0.50-0.99) compared with an intake of less than once per month. In contrast, fried fish/fish sandwich consumption was positively associated with total stroke (P = .006) and ischemic stroke (P = .003), with a 44\% higher risk of ischemic stroke with consumption of more than once per week (HR, 1.44; 95\% CI, 1.12-1.85) compared with consumption of less than once per month. Fish consumption was not associated with hemorrhagic stroke.

CONCLUSIONS: Among elderly individuals, consumption of tuna or other broiled or baked fish is associated with lower risk of ischemic stroke, while intake of fried fish or fish sandwiches is associated with higher risk. These results suggest that fish consumption may influence stroke risk late in life; potential mechanisms and alternate explanations warrant further study.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Animals, Cohort Studies, Confidence Intervals, Diet, Fatty Acids, Omega-3, Female, Fish Oils, Fishes, Humans, Incidence, Male, Multivariate Analysis, Probability, Proportional Hazards Models, Risk Assessment, Seafood, Sensitivity and Specificity, Sex Distribution, Stroke, Surveys and Questionnaires, Survival Rate, United States}, issn = {0003-9926}, doi = {10.1001/archinte.165.2.200}, author = {Mozaffarian, Dariush and Longstreth, W T and Lemaitre, Rozenn N and Manolio, Teri A and Kuller, Lewis H and Burke, Gregory L and Siscovick, David S} } @article {843, title = {Fish intake and risk of incident heart failure.}, journal = {J Am Coll Cardiol}, volume = {45}, year = {2005}, month = {2005 Jun 21}, pages = {2015-21}, abstract = {

OBJECTIVES: Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).

BACKGROUND: The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.

METHODS: Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.

RESULTS: During 12 years{\textquoteright} follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20\% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95\% confidence interval [CI] = 0.64 to 0.99), 31\% lower risk with intake 3 to 4 times/week (HR = 0.69, 95\% CI = 0.52 to 0.91), and 32\% lower risk with intake > or =5 times/week (HR = 0.68, 95\% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37\% lower risk in the highest quintile of intake (HR = 0.73, 95\% CI = 0.57 to 0.94) compared with the lowest.

CONCLUSIONS: Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.

}, keywords = {Aged, Animals, Cohort Studies, Cooking, Diet, Diet Surveys, Disease-Free Survival, Female, Fishes, Heart Failure, Humans, Incidence, Male, Risk Factors, United States}, issn = {0735-1097}, doi = {10.1016/j.jacc.2005.03.038}, author = {Mozaffarian, Dariush and Bryson, Chris L and Lemaitre, Rozenn N and Burke, Gregory L and Siscovick, David S} } @article {893, title = {Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death.}, journal = {Circulation}, volume = {113}, year = {2006}, month = {2006 Apr 18}, pages = {1842-8}, abstract = {

BACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.

METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4\% and 57.1\% among white and 50.1\% and 81.4\% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95\% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95\% CI, 1.18 to 2.23) and black (HR, 1.23; 95\% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95\% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.

CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.

}, keywords = {African Continental Ancestry Group, Aged, Case-Control Studies, Death, Sudden, Cardiac, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Glutamine, Haplotypes, Homozygote, Humans, Male, Polymorphism, Single Nucleotide, Receptors, Adrenergic, beta-2, Reproducibility of Results}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.105.582833}, author = {Sotoodehnia, Nona and Siscovick, David S and Vatta, Matteo and Psaty, Bruce M and Tracy, Russell P and Towbin, Jeffrey A and Lemaitre, Rozenn N and Rea, Thomas D and Durda, J Peter and Chang, Joel M and Lumley, Thomas S and Kuller, Lewis H and Burke, Gregory L and Heckbert, Susan R} } @article {903, title = {Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {114}, year = {2006}, month = {2006 Jul 18}, pages = {209-15}, abstract = {

BACKGROUND: Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death.

METHODS AND RESULTS: We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95\% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95\% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95\% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95\% CI 0.06 to 0.54).

CONCLUSIONS: Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Coronary Disease, Death, Sudden, Cardiac, Female, Humans, Male, Myocardial Ischemia, Phospholipids, Trans Fatty Acids, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.106.620336}, author = {Lemaitre, Rozenn N and King, Irena B and Mozaffarian, Dariush and Sotoodehnia, Nona and Rea, Thomas D and Kuller, Lewis H and Tracy, Russel P and Siscovick, David S} } @article {1238, title = {Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes.}, journal = {Am J Clin Nutr}, volume = {92}, year = {2010}, month = {2010 Dec}, pages = {1350-8}, abstract = {

BACKGROUND: Animal experiments suggest that circulating palmitoleic acid (cis-16:1n-7) from adipocyte de novo fatty acid synthesis may directly regulate insulin resistance and metabolic dysregulation.

OBJECTIVE: We investigated the independent determinants of circulating palmitoleate in free-living humans and whether palmitoleate is related to lower metabolic risk and the incidence of diabetes.

DESIGN: In a prospective cohort of 3630 US men and women in the Cardiovascular Health Study, plasma phospholipid fatty acids, anthropometric variables, blood lipids, inflammatory markers, and glucose and insulin concentrations were measured between 1992 and 2006 by using standardized methods. Independent determinants of plasma phospholipid palmitoleate and relations of palmitoleate with metabolic risk factors were investigated by using multivariable-adjusted linear regression. Relations with incident diabetes (296 incident cases) were investigated by using Cox proportional hazards.

RESULTS: The mean ({\textpm} SD) palmitoleate value was 0.49 {\textpm} 0.20\% (range: 0.11-2.55\%) of total fatty acids. Greater body mass index, carbohydrate intake, protein intake, and alcohol use were each independent lifestyle correlates of higher palmitoleate concentrations. In multivariable analyses that adjusted for these factors and other potential confounders, higher palmitoleate concentrations were independently associated with lower LDL cholesterol (P < 0.001), higher HDL cholesterol (P < 0.001), lower total:HDL-cholesterol ratio (P = 0.04), and lower fibrinogen (P < 0.001). However, palmitoleate was also associated with higher triglycerides (P < 0.001) and (in men only) with greater insulin resistance (P < 0.001). Palmitoleate was not significantly associated with incident diabetes.

CONCLUSIONS: Adiposity (energy imbalance), carbohydrate consumption, and alcohol use-even within typical ranges-are associated with higher circulating palmitoleate concentrations. Circulating palmitoleate is robustly associated with multiple metabolic risk factors but in mixed directions, perhaps related to divergent lifestyle determinants or endogenous sources (liver, adipose tissue) of fatty acid synthesis.

}, keywords = {Aged, Aged, 80 and over, Alcohol Drinking, Body Mass Index, Cholesterol, Cholesterol, HDL, Diabetes Mellitus, Diet, Dietary Carbohydrates, Fatty Acids, Monounsaturated, Female, Fibrinogen, Humans, Insulin Resistance, Life Style, Lipids, Male, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.110.003970}, author = {Mozaffarian, Dariush and Cao, Haiming and King, Irena B and Lemaitre, Rozenn N and Song, Xiaoling and Siscovick, David S and Hotamisligil, G{\"o}khan S} } @article {1172, title = {Food sources of individual plasma phospholipid trans fatty acid isomers: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {91}, year = {2010}, month = {2010 Apr}, pages = {883-93}, abstract = {

BACKGROUND: The overall consumption of trans fatty acids (TFAs) increases the risk of coronary artery disease. However, multiple TFA isomers exist, each with potentially different health effects. Different food sources of these specific TFA isomers are not well established.

OBJECTIVE: Our objective was to determine the major independent food sources of specific TFA isomers.

DESIGN: We investigated relations of major potential food sources of TFAs, as assessed by serial food-frequency questionnaires, with 10 plasma phospholipid TFA isomers [5 trans (t-) 18:1, 3 t-18:2, and 2 t-16:1] in 3330 older adults in the Cardiovascular Health Study, a community-based multicenter cohort. Stepwise regression was used to identify independent major food sources of individual plasma phospholipid TFA isomers, which were adjusted for demographic, lifestyle, and dietary factors.

RESULTS: All 5 t-18:1 isomers were similarly associated with foods commonly made with partially hydrogenated vegetable oils (PHVOs), including biscuits (0.51 higher SD of total 18:1 fatty acid concentrations per serving/d, P < 0.01), chips and/or popcorn (0.33 higher SD per serving/d, P = 0.02), margarine (0.32 higher SD per serving/d, P < 0.001), fried foods (0.32 higher SD per serving/d, P = 0.04), and bakery foods (0.23 higher SD per serving/d, P = 0.02). Each of the t-18:2 isomers were associated only with bakery foods (0.50 higher SD of total 18:2 fatty acid concentrations per serving/d, P < 0.001). Ruminant foods were major correlates of t-16:1n-7, including red meats (0.72 higher SD per serving/d, P < 0.001), butter (0.43 higher SD per serving/d, P < 0.001), and higher-fat dairy (0.37 higher SD per serving/d, P < 0.001). In contrast, t-16:1n-9 were derived mainly from margarine (0.31 higher SD per serving/d, P < 0.001).

CONCLUSIONS: t-18:1 Isomers are similarly derived from multiple PHVO-containing foods. In contrast, t-18:2 and t-16:1n-9 isomers are derived from more-specific types of PHVO-containing foods. Ruminant foods are major sources of t-16:1n-7. Different TFA isomers and dietary sources should be considered when investigating health effects and interventions to lower TFAs.

}, keywords = {Aged, Cardiovascular System, Diet, Diet Surveys, Dietary Fats, Female, Food Analysis, Health, Humans, Hydrogenation, Isomerism, Male, Phospholipids, Plant Oils, Regression Analysis, Surveys and Questionnaires, Trans Fatty Acids}, issn = {1938-3207}, doi = {10.3945/ajcn.2009.28877}, author = {Micha, Renata and King, Irena B and Lemaitre, Rozenn N and Rimm, Eric B and Sacks, Frank and Song, Xiaoling and Siscovick, David S and Mozaffarian, Dariush} } @article {1222, title = {Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.}, journal = {Diabetes Care}, volume = {33}, year = {2010}, month = {2010 Dec}, pages = {2684-91}, abstract = {

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising \~{} 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95\% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

}, keywords = {Adult, Aged, Blood Glucose, Edible Grain, European Continental Ancestry Group, Fasting, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1935-5548}, doi = {10.2337/dc10-1150}, author = {Nettleton, Jennifer A and McKeown, Nicola M and Kanoni, Stavroula and Lemaitre, Rozenn N and Hivert, Marie-France and Ngwa, Julius and van Rooij, Frank J A and Sonestedt, Emily and Wojczynski, Mary K and Ye, Zheng and Tanaka, Tosh and Garcia, Melissa and Anderson, Jennifer S and Follis, Jack L and Djouss{\'e}, Luc and Mukamal, Kenneth and Papoutsakis, Constantina and Mozaffarian, Dariush and Zillikens, M Carola and Bandinelli, Stefania and Bennett, Amanda J and Borecki, Ingrid B and Feitosa, Mary F and Ferrucci, Luigi and Forouhi, Nita G and Groves, Christopher J and Hallmans, G{\"o}ran and Harris, Tamara and Hofman, Albert and Houston, Denise K and Hu, Frank B and Johansson, Ingegerd and Kritchevsky, Stephen B and Langenberg, Claudia and Launer, Lenore and Liu, Yongmei and Loos, Ruth J and Nalls, Michael and Orho-Melander, Marju and Renstrom, Frida and Rice, Kenneth and Riserus, Ulf and Rolandsson, Olov and Rotter, Jerome I and Saylor, Georgia and Sijbrands, Eric J G and Sjogren, Per and Smith, Albert and Steingr{\'\i}msd{\'o}ttir, Laufey and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Prokopenko, Inga and Pankow, James S and van Duijn, Cornelia M and Florez, Jose C and Witteman, Jacqueline C M and Dupuis, Jos{\'e}e and Dedoussis, George V and Ordovas, Jose M and Ingelsson, Erik and Cupples, L Adrienne and Siscovick, David S and Franks, Paul W and Meigs, James B} } @article {1257, title = {Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study.}, journal = {Ann Intern Med}, volume = {153}, year = {2010}, month = {2010 Dec 21}, pages = {790-9}, abstract = {

BACKGROUND: Palmitoleic acid (cis-16:1n-7), which is produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative.

OBJECTIVE: To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes.

DESIGN: Prospective cohort study from 1992 to 2006.

SETTING: Four U.S. communities.

PATIENTS: 3736 adults in the Cardiovascular Health Study.

MEASUREMENTS: Anthropometric characteristics and levels of plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose-insulin measured at baseline in 1992 and dietary habits measured 3 years earlier. Multivariate-adjusted models were used to investigate how demographic, clinical, and lifestyle factors independently related to plasma phospholipid trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). Findings were validated for metabolic risk factors in an independent cohort of 327 women.

RESULTS: In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels (1.9\% across quintiles; P = 0.040), lower triglyceride levels (-19.0\%; P < 0.001), a lower total cholesterol-HDL cholesterol ratio (-4.7\%; P < 0.001), lower C-reactive protein levels (-13.8\%; P = 0.05), and lower insulin resistance (-16.7\%, P < 0.001). Trans-palmitoleate was also associated with a substantially lower incidence of diabetes, with multivariate hazard ratios of 0.41 (95\% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5 versus quintile 1 (P for trend < 0.001). Findings were independent of estimated dairy consumption or other fatty acid dairy biomarkers. Protective associations with metabolic risk factors were confirmed in the validation cohort.

LIMITATION: Results could be affected by measurement error or residual confounding.

CONCLUSION: Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

}, keywords = {Adiposity, Aged, C-Reactive Protein, Cholesterol, Cholesterol, HDL, Dairy Products, Diabetes Mellitus, Type 2, Fatty Acids, Monounsaturated, Feeding Behavior, Female, Humans, Incidence, Insulin Resistance, Male, Prospective Studies, Risk Factors, Triglycerides, United States}, issn = {1539-3704}, doi = {10.7326/0003-4819-153-12-201012210-00005}, author = {Mozaffarian, Dariush and Cao, Haiming and King, Irena B and Lemaitre, Rozenn N and Song, Xiaoling and Siscovick, David S and Hotamisligil, G{\"o}khan S} } @article {1309, title = {Circulating long-chain ω-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study.}, journal = {Ann Intern Med}, volume = {155}, year = {2011}, month = {2011 Aug 02}, pages = {160-70}, abstract = {

BACKGROUND: Few previous studies have evaluated associations between long-chain ω-3 fatty acids and incidence of congestive heart failure (CHF), and those that have are typically based on diet questionnaires and yield conflicting results. Circulating fatty acid concentrations provide objective biomarkers of exposure.

OBJECTIVE: To determine whether plasma phospholipid concentrations of long-chain ω-3 fatty acids, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), were associated with incident CHF.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PATIENTS: 2735 U.S. adults without prevalent heart disease who were enrolled in the Cardiovascular Health Study from 1992 to 2006.

MEASUREMENTS: Plasma phospholipid fatty acid concentrations and other cardiovascular risk factors were measured in 1992 by using standardized methods. Relationships with incident CHF (555 cases during 26 490 person-years, adjudicated by using medical records) were assessed by using Cox proportional hazards models.

RESULTS: After multivariate adjustment, plasma phospholipid EPA concentration was inversely associated with incident CHF; risk was approximately 50\% lower in the highest versus the lowest quartile (hazard ratio [HR], 0.52 [95\% CI, 0.38 to 0.72]; P for trend = 0.001). In similar analyses, trends toward lower risk were seen for DPA (HR, 0.76 [CI, 0.56 to 1.04]; P for trend = 0.057) and total long-chain ω-3 fatty acids (HR, 0.70 [CI, 0.49 to 0.99]; P for trend = 0.062) but not for DHA (HR, 0.84 [CI, 0.58 to 1.21]; P for trend = 0.38). In analyses censored to the middle of follow-up (7 years) to minimize exposure misclassification over time, multivariate-adjusted HRs were 0.48 for EPA (CI, 0.32 to 0.71; P for trend = 0.005), 0.61 for DPA (CI, 0.39 to 0.95; P for trend = 0.033), 0.64 for DHA (CI, 0.40 to 1.04; P for trend = 0.057), and 0.51 for total ω-3 fatty acids (CI, 0.32 to 0.80; P for trend = 0.003).

LIMITATIONS: Temporal changes in fatty acid concentrations over time may have caused underestimation of associations. Unmeasured or imperfectly measured covariates may have caused residual confounding.

CONCLUSION: Circulating individual and total ω-3 fatty acid concentrations are associated with lower incidence of CHF in older adults.

PRIMARY FUNDING SOURCE: National Institutes of Health.

}, keywords = {Aged, Biomarkers, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Feeding Behavior, Heart Failure, Humans, Incidence, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1539-3704}, doi = {10.7326/0003-4819-155-3-201108020-00006}, author = {Mozaffarian, Dariush and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Spiegelman, Donna and Sacks, Frank M and Rimm, Eric B and Siscovick, David S} } @article {1299, title = {Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {94}, year = {2011}, month = {2011 Aug}, pages = {431-8}, abstract = {

BACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown.

OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA.

DESIGN: A community-based prospective study was conducted in 2890 men and women aged >=65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards.

RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95\% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes.

CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Coronary Disease, Death, Sudden, Cardiac, Diet, Fatty Acids, Female, Humans, Lipogenesis, Male, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1938-3207}, doi = {10.3945/ajcn.111.012054}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and Imamura, Fumiaki and King, Irena B and Song, Xiaoling and Spiegelman, Donna and Siscovick, David S and Mozaffarian, Dariush} } @article {1311, title = {Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jul}, pages = {e1002193}, abstract = {

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10$^{-}$$^{6}$$^{4}$) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10$^{-}$$^{5}$$^{8}$) and docosapentaenoic acid (DPA, p = 4 x 10$^{-}${\textonesuperior}$^{5}$$^{4}$). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10$^{-}${\textonesuperior}{\texttwosuperior}) and DPA (p = 1 x 10$^{-}$$^{4}${\textthreesuperior}) and lower docosahexaenoic acid (DHA, p = 1 x 10$^{-}${\textonesuperior}$^{5}$). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10$^{-}$$^{8}$). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

}, keywords = {Alleles, Continental Population Groups, Fatty Acids, Omega-3, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002193}, author = {Lemaitre, Rozenn N and Tanaka, Toshiko and Tang, Weihong and Manichaikul, Ani and Foy, Millennia and Kabagambe, Edmond K and Nettleton, Jennifer A and King, Irena B and Weng, Lu-Chen and Bhattacharya, Sayanti and Bandinelli, Stefania and Bis, Joshua C and Rich, Stephen S and Jacobs, David R and Cherubini, Antonio and McKnight, Barbara and Liang, Shuang and Gu, Xiangjun and Rice, Kenneth and Laurie, Cathy C and Lumley, Thomas and Browning, Brian L and Psaty, Bruce M and Chen, Yii-der I and Friedlander, Yechiel and Djouss{\'e}, Luc and Wu, Jason H Y and Siscovick, David S and Uitterlinden, Andr{\'e} G and Arnett, Donna K and Ferrucci, Luigi and Fornage, Myriam and Tsai, Michael Y and Mozaffarian, Dariush and Steffen, Lyn M} } @article {1291, title = {Plasma omega-3 fatty acids and incident diabetes in older adults.}, journal = {Am J Clin Nutr}, volume = {94}, year = {2011}, month = {2011 Aug}, pages = {527-33}, abstract = {

BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs.

OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes.

DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks.

RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95\% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95\% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03).

CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.

}, keywords = {Aged, Aged, 80 and over, alpha-Linolenic Acid, Diabetes Mellitus, Fatty Acids, Omega-3, Female, Humans, Male, Phospholipids, Proportional Hazards Models, Prospective Studies}, issn = {1938-3207}, doi = {10.3945/ajcn.111.013334}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Ix, Joachim H and Mukamal, Kenneth J and Siscovick, David S and Mozaffarian, Dariush} } @article {1308, title = {Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.}, journal = {Diabetes}, volume = {60}, year = {2011}, month = {2011 Sep}, pages = {2407-16}, abstract = {

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient {\textpm} SE per 1 mg/day of zinc intake: -0.0012 {\textpm} 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient {\textpm} SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 {\textpm} 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

}, keywords = {Blood Glucose, Cation Transport Proteins, Cohort Studies, Humans, Polymorphism, Single Nucleotide, Zinc, Zinc Transporter 8}, issn = {1939-327X}, doi = {10.2337/db11-0176}, author = {Kanoni, Stavroula and Nettleton, Jennifer A and Hivert, Marie-France and Ye, Zheng and van Rooij, Frank J A and Shungin, Dmitry and Sonestedt, Emily and Ngwa, Julius S and Wojczynski, Mary K and Lemaitre, Rozenn N and Gustafsson, Stefan and Anderson, Jennifer S and Tanaka, Toshiko and Hindy, George and Saylor, Georgia and Renstrom, Frida and Bennett, Amanda J and van Duijn, Cornelia M and Florez, Jose C and Fox, Caroline S and Hofman, Albert and Hoogeveen, Ron C and Houston, Denise K and Hu, Frank B and Jacques, Paul F and Johansson, Ingegerd and Lind, Lars and Liu, Yongmei and McKeown, Nicola and Ordovas, Jose and Pankow, James S and Sijbrands, Eric J G and Syv{\"a}nen, Ann-Christine and Uitterlinden, Andr{\'e} G and Yannakoulia, Mary and Zillikens, M Carola and Wareham, Nick J and Prokopenko, Inga and Bandinelli, Stefania and Forouhi, Nita G and Cupples, L Adrienne and Loos, Ruth J and Hallmans, G{\"o}ran and Dupuis, Jos{\'e}e and Langenberg, Claudia and Ferrucci, Luigi and Kritchevsky, Stephen B and McCarthy, Mark I and Ingelsson, Erik and Borecki, Ingrid B and Witteman, Jacqueline C M and Orho-Melander, Marju and Siscovick, David S and Meigs, James B and Franks, Paul W and Dedoussis, George V} } @article {1362, title = {Association of plasma phospholipid long-chain ω-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 Mar 06}, pages = {1084-93}, abstract = {

BACKGROUND: Experimental studies suggest that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may reduce the risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFAs provide an objective measurement of exposure.

METHODS AND RESULTS: Among 3326 US men and women >=65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid) levels was 0.71 (95\% confidence interval, 0.57-0.89; P for trend=0.004) and of DHA levels was 0.77 (95\% confidence interval, 0.62-0.96; P for trend=0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.

CONCLUSIONS: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Dietary Fats, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Risk Factors, Seafood}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.111.062653}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Sacks, Frank M and Rimm, Eric B and Heckbert, Susan R and Siscovick, David S and Mozaffarian, Dariush} } @article {1396, title = {Circulating and dietary α-linolenic acid and incidence of congestive heart failure in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {96}, year = {2012}, month = {2012 Aug}, pages = {269-74}, abstract = {

BACKGROUND: Few studies have evaluated the association between the n-3 fatty acid α-linolenic acid (ALA) and the incidence of congestive heart failure (CHF).

OBJECTIVE: We investigated whether plasma phospholipid concentrations and estimated dietary consumption of ALA are associated with incident CHF.

DESIGN: We used data from the Cardiovascular Health Study, a prospective cohort study of cardiovascular diseases among adults aged >=65 y, from 4 US communities. A total of 2957 participants free of prevalent heart disease and with available fatty acid measurements were included in biomarker analyses (30,722 person-years and 686 incident CHF events). A total of 4432 participants free of prevalent heart disease were included in dietary analyses (52,609 person-years and 1072 events). We investigated the association of ALA with incident CHF by using Cox regression.

RESULTS: After adjustment for age, sex, race, education, smoking status, BMI, waist circumference, and alcohol consumption, plasma phospholipid ALA was not associated with incident CHF (HR for the highest compared with the lowest quartile: 0.97; 95\% CI: 0.79, 1.21; P-trend = 0.85). Likewise, dietary ALA was not associated with incident CHF (adjusted HR for the highest compared with the lowest quartile: 0.96; 95\% CI: 0.82, 1.20; P-trend = 0.97). We observed no association of biomarker or dietary ALA with nonvalvular CHF subtype. We also found little evidence of an association between ALA and CHF in subgroups based on age, sex, diabetes, fish consumption, BMI, or FADS2 genotype (rs1535).

CONCLUSION: ALA intake is not associated with incident CHF in older adults. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Alcohol Drinking, alpha-Linolenic Acid, Biomarkers, Body Mass Index, Cardiovascular Diseases, Diet, Fatty Acid Desaturases, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Polymorphism, Single Nucleotide, Prevalence, Prospective Studies, Risk Factors, Smoking, Surveys and Questionnaires, United States}, issn = {1938-3207}, doi = {10.3945/ajcn.112.037960}, author = {Lemaitre, Rozenn N and Sitlani, Colleen and Song, Xiaoling and King, Irena B and McKnight, Barbara and Spiegelman, Donna and Sacks, Frank M and Djouss{\'e}, Luc and Rimm, Eric B and Siscovick, David S and Mozaffarian, Dariush} } @article {1361, title = {Nonesterified fatty acids and risk of sudden cardiac death in older adults.}, journal = {Circ Arrhythm Electrophysiol}, volume = {5}, year = {2012}, month = {2012 Apr}, pages = {273-8}, abstract = {

BACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.

METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95\% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.

CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Death, Sudden, Cardiac, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Retrospective Studies, Risk Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.111.967661}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Ix, Joachim H and Kizer, Jorge R and Lemaitre, Rozenn N and Sotoodehnia, Nona and Zieman, Susan J and Mozaffarian, Dariush and Tracy, Russell P and Mukamal, Kenneth J and Siscovick, David S} } @article {1410, title = {Novel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {96}, year = {2012}, month = {2012 Dec}, pages = {1252-61}, abstract = {

BACKGROUND: Complex interplays of diet and metabolism influence circulating fatty acids (FAs), possibly constituting FA patterns related to cardiovascular disease (CVD) risk.

OBJECTIVES: We aimed to derive FA patterns from circulating FAs, relate the patterns to CVD incidence, and extend the derived patterns to atherosclerosis progression in another independent cohort.

DESIGN: We used principal component analysis (PCA) to derive FA patterns from 38 plasma phospholipid FAs in 2972 older adults in the Cardiovascular Health Study (CHS). Identified patterns were evaluated for prospective associations with 14-y incidence of CVD [ischemic heart disease (IHD) or stroke]. In another independent cohort of postmenopausal women with IHD, we evaluated associations of the CHS-derived patterns with 3.2-y progression of angiographically defined coronary atherosclerosis.

RESULTS: Three distinct patterns were identified, characterized by higher proportions of trans FAs, de novo lipogenesis (DNL) FAs, and long-chain MUFAs (LCMUFAs). During 32,265 person-years, 780 incident CVD events occurred. The trans FA pattern was associated with higher CVD risk (multivariable-adjusted HR for the highest compared with the lowest quintiles = 1.58; 95\% CI: 1.17, 2.12; P-trend = 0.006), primarily attributable to higher risk of stroke (HR: 2.46; 95\% CI: 1.54, 3.92; P-trend = 0.005). The DNL and LCMUFA patterns were not associated with CVD incidence or with IHD or stroke (P-trend > 0.11 each). In the second cohort, the trans FA pattern, but not the other 2 patterns, was positively associated with progression of coronary atherosclerosis (P-trend < 0.05).

CONCLUSIONS: PCA appears to provide informative circulating FA patterns. A pattern driven mainly by trans FA levels related to greater CVD risk in older adults and coronary atherosclerosis progression in women with IHD.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cohort Studies, Coronary Artery Disease, Disease Progression, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Myocardial Ischemia, Principal Component Analysis, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, Trans Fatty Acids, United States}, issn = {1938-3207}, doi = {10.3945/ajcn.112.039990}, author = {Imamura, Fumiaki and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Lichtenstein, Alice H and Matthan, Nirupa R and Herrington, David M and Siscovick, David S and Mozaffarian, Dariush} } @article {1397, title = {Trans-fatty acid consumption and heart rate variability in 2 separate cohorts of older and younger adults.}, journal = {Circ Arrhythm Electrophysiol}, volume = {5}, year = {2012}, month = {2012 Aug 01}, pages = {728-38}, abstract = {

BACKGROUND: Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cell membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain understudied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, was independently associated with HRV in 2 independent cohorts in the United States and Portugal.

METHODS AND RESULTS: In 2 independent cohorts of older US adults (Cardiovascular Health Study [CHS], age 72{\textpm}5 years, 1989/1995) and young Portuguese adults (Porto, age 19{\textpm}2 years, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2 but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (n=1076) and repeated short-term (5-minute) ECGs in Porto (n=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour SD of all normal-to-normal intervals both cross-sectionally (-12\%; 95\% CI, -19\% to -6\%; P=0.001) and longitudinally (-15\%; 95\% CI, -25\% to -4\%; P= 0.009) and lower 24-hour SD of 5-minute average N-N intervals and mean of the 5-minute SD of N-N intervals calculated over 24 hours (P<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV in particular time-domain indices (24-hour SD of all normal-to-normal intervals, SD of 5-minute average N-N intervals, mean of the 5-minute SD of N-N intervals calculated over 24 hours; P<0.05 each). In Porto, each higher SD TFA consumption was associated with 4\% lower 5-minute 24-hour SD of all normal-to-normal intervals (95\% CI, -8\% to -1\%; P=0.04) and 7\% lower 5-minute square root of the mean of the squares of successive N-N differences (95\% CI, -13\% to -1\%; P=0.04).

CONCLUSIONS: Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV-related mechanisms, whereby trans-18:2 may increase arrhythmic risk.

}, keywords = {Adolescent, Age Factors, Aged, Aging, Arrhythmias, Cardiac, Cohort Studies, Cross-Sectional Studies, Dietary Fats, Electrocardiography, Ambulatory, Feeding Behavior, Female, Heart Rate, Humans, Linear Models, Longitudinal Studies, Male, Multivariate Analysis, Portugal, Predictive Value of Tests, Prospective Studies, Risk Assessment, Risk Factors, Surveys and Questionnaires, Trans Fatty Acids, United States, Young Adult}, issn = {1941-3084}, doi = {10.1161/CIRCEP.111.966259}, author = {Soares-Miranda, Luisa and Stein, Phyllis K and Imamura, Fumiaki and Sattelmair, Jacob and Lemaitre, Rozenn N and Siscovick, David S and Mota, Jorge and Mozaffarian, Dariush} } @article {5846, title = {Associations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Jan 31}, pages = {e003814}, abstract = {

BACKGROUND: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).

METHODS AND RESULTS: The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95\% CI, 0.90 to 1.37), 1.09 (95\% CI, 0.88 to 1.35), and 0.92 (95\% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.

CONCLUSIONS: Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.

}, keywords = {Age Factors, Aged, Aged, 80 and over, alpha-Linolenic Acid, Atrial Fibrillation, Biomarkers, Diet, Female, Humans, Incidence, Linear Models, Longitudinal Studies, Male, Nutritional Status, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.112.003814}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Heckbert, Susan R and McKnight, Barbara and King, Irena B and Rimm, Eric B and Psaty, Bruce M and Sacks, Frank M and Song, Xiaoling and Spiegelman, Donna and Lemaitre, Rozenn N} } @article {6177, title = {Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Oct 10}, pages = {e000305}, abstract = {

BACKGROUND: Consumption of tuna or other broiled or baked fish, but not fried fish, is associated with fewer subclinical brain abnormalities on magnetic resonance imaging (MRI). We investigated the association between plasma phospholipid omega-3 polyunsaturated fatty acids (PUFAs), objective biomarkers of exposure, and subclinical brain abnormalities on MRI.

METHODS AND RESULTS: In the community-based Cardiovascular Health Study, 3660 participants aged >= 65 underwent brain MRI in 1992-1994, and 2313 were rescanned 5 years later. MRIs were centrally read by neuroradiologists in a standardized, blinded manner. Participants with recognized transient ischemic attacks or stroke were excluded. Phospholipid PUFAs were measured in stored plasma collected in 1992-1993 and related to cross-sectional and longitudinal MRI findings. After multivariable adjustment, the odds ratio for having a prevalent subclinical infarct was 0.60 (95\% CI, 0.44 to 0.82; P for trend = 0.001) in the highest versus lowest long-chain omega-3 PUFA quartile. Higher long-chain omega-3 PUFA content was also associated with better white matter grade, but not with sulcal or ventricular grades, markers of brain atrophy, or with incident subclinical infarcts. The phospholipid intermediate-chain omega-3 PUFA alpha-linolenic acid was associated only with modestly better sulcal and ventricular grades. However, this finding was not supported in the analyses with alpha-linolenic acid intake.

CONCLUSIONS: Among older adults, higher phospholipid long-chain omega-3 PUFA content was associated with lower prevalence of subclinical infarcts and better white matter grade on MRI. Our results support the beneficial effects of fish consumption, the major source of long-chain omega-3 PUFAs, on brain health in later life. The role of plant-derived alpha-linolenic acid in brain health requires further investigation.

}, keywords = {Aged, Animals, Biomarkers, Brain, Cross-Sectional Studies, Fatty Acids, Omega-3, Female, Fishes, Humans, Magnetic Resonance Imaging, Male, Prospective Studies}, issn = {2047-9980}, doi = {10.1161/JAHA.113.000305}, author = {Virtanen, Jyrki K and Siscovick, David S and Lemaitre, Rozenn N and Longstreth, William T and Spiegelman, Donna and Rimm, Eric B and King, Irena B and Mozaffarian, Dariush} } @article {5880, title = {Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu}, journal = {Circ Cardiovasc Genet}, volume = {6}, year = {2013}, month = {2013 Apr}, pages = {171-83}, abstract = {

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of >=1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7{\texttimes}10(-11)) and lower 18:0 (P=2.2{\texttimes}10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6{\texttimes}10(-13)) and 18:1n-9 (P=2.2{\texttimes}10(-32)) and lower 18:0 (P=1.3{\texttimes}10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8{\texttimes}10(-9)). GCKR (glucokinase regulator; P=9.8{\texttimes}10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7{\texttimes}10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7{\texttimes}10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1{\texttimes}10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 2, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, Fatty Acids, Monounsaturated, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Lipogenesis, Male, Middle Aged, Oleic Acid, Palmitic Acid, Polymorphism, Single Nucleotide, Stearic Acids}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.964619}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and Manichaikul, Ani and Guan, Weihua and Tanaka, Toshiko and Foy, Millennia and Kabagambe, Edmond K and Djouss{\'e}, Luc and Siscovick, David and Fretts, Amanda M and Johnson, Catherine and King, Irena B and Psaty, Bruce M and McKnight, Barbara and Rich, Stephen S and Chen, Yii-der I and Nettleton, Jennifer A and Tang, Weihong and Bandinelli, Stefania and Jacobs, David R and Browning, Brian L and Laurie, Cathy C and Gu, Xiangjun and Tsai, Michael Y and Steffen, Lyn M and Ferrucci, Luigi and Fornage, Myriam and Mozaffarian, Dariush} } @article {6163, title = {Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.}, journal = {Am J Clin Nutr}, volume = {97}, year = {2013}, month = {2013 Jun}, pages = {1395-402}, abstract = {

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 {\texttimes} 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β {\textpm} SE: 0.25 {\textpm} 0.04\%; P = 1.68 {\texttimes} 10(-8)) and lower fat (β {\textpm} SE: -0.21 {\textpm} 0.04\%; P = 1.57 {\texttimes} 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β {\textpm} SE: 0.10 {\textpm} 0.02\%; P = 9.96 {\texttimes} 10(-10)), independent of BMI (after adjustment for BMI, β {\textpm} SE: 0.08 {\textpm} 0.02\%; P = 3.15 {\texttimes} 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

}, keywords = {Alleles, Atherosclerosis, Body Mass Index, Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Fibroblast Growth Factors, Follow-Up Studies, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Life Style, Obesity, Polymorphism, Single Nucleotide, Prospective Studies, Quantitative Trait Loci, Surveys and Questionnaires}, issn = {1938-3207}, doi = {10.3945/ajcn.112.052183}, author = {Tanaka, Toshiko and Ngwa, Julius S and van Rooij, Frank J A and Zillikens, M Carola and Wojczynski, Mary K and Frazier-Wood, Alexis C and Houston, Denise K and Kanoni, Stavroula and Lemaitre, Rozenn N and Luan, Jian{\textquoteright}an and Mikkil{\"a}, Vera and Renstrom, Frida and Sonestedt, Emily and Zhao, Jing Hua and Chu, Audrey Y and Qi, Lu and Chasman, Daniel I and de Oliveira Otto, Marcia C and Dhurandhar, Emily J and Feitosa, Mary F and Johansson, Ingegerd and Khaw, Kay-Tee and Lohman, Kurt K and Manichaikul, Ani and McKeown, Nicola M and Mozaffarian, Dariush and Singleton, Andrew and Stirrups, Kathleen and Viikari, Jorma and Ye, Zheng and Bandinelli, Stefania and Barroso, In{\^e}s and Deloukas, Panos and Forouhi, Nita G and Hofman, Albert and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and North, Kari E and Dimitriou, Maria and Hallmans, G{\"o}ran and K{\"a}h{\"o}nen, Mika and Langenberg, Claudia and Ordovas, Jose M and Uitterlinden, Andr{\'e} G and Hu, Frank B and Kalafati, Ioanna-Panagiota and Raitakari, Olli and Franco, Oscar H and Johnson, Andrew and Emilsson, Valur and Schrack, Jennifer A and Semba, Richard D and Siscovick, David S and Arnett, Donna K and Borecki, Ingrid B and Franks, Paul W and Kritchevsky, Stephen B and Lehtim{\"a}ki, Terho and Loos, Ruth J F and Orho-Melander, Marju and Rotter, Jerome I and Wareham, Nicholas J and Witteman, Jacqueline C M and Ferrucci, Luigi and Dedoussis, George and Cupples, L Adrienne and Nettleton, Jennifer A} } @article {5879, title = {Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.}, journal = {J Nutr}, volume = {143}, year = {2013}, month = {2013 Mar}, pages = {345-53}, abstract = {

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95\% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95\% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

}, keywords = {Blood Glucose, Female, Genetic Loci, Humans, Insulin, Magnesium, Male, Polymorphism, Single Nucleotide, Trace Elements, TRPM Cation Channels}, issn = {1541-6100}, doi = {10.3945/jn.112.172049}, author = {Hruby, Adela and Ngwa, Julius S and Renstrom, Frida and Wojczynski, Mary K and Ganna, Andrea and Hallmans, G{\"o}ran and Houston, Denise K and Jacques, Paul F and Kanoni, Stavroula and Lehtim{\"a}ki, Terho and Lemaitre, Rozenn N and Manichaikul, Ani and North, Kari E and Ntalla, Ioanna and Sonestedt, Emily and Tanaka, Toshiko and van Rooij, Frank J A and Bandinelli, Stefania and Djouss{\'e}, Luc and Grigoriou, Efi and Johansson, Ingegerd and Lohman, Kurt K and Pankow, James S and Raitakari, Olli T and Riserus, Ulf and Yannakoulia, Mary and Zillikens, M Carola and Hassanali, Neelam and Liu, Yongmei and Mozaffarian, Dariush and Papoutsakis, Constantina and Syv{\"a}nen, Ann-Christine and Uitterlinden, Andr{\'e} G and Viikari, Jorma and Groves, Christopher J and Hofman, Albert and Lind, Lars and McCarthy, Mark I and Mikkil{\"a}, Vera and Mukamal, Kenneth and Franco, Oscar H and Borecki, Ingrid B and Cupples, L Adrienne and Dedoussis, George V and Ferrucci, Luigi and Hu, Frank B and Ingelsson, Erik and K{\"a}h{\"o}nen, Mika and Kao, W H Linda and Kritchevsky, Stephen B and Orho-Melander, Marju and Prokopenko, Inga and Rotter, Jerome I and Siscovick, David S and Witteman, Jacqueline C M and Franks, Paul W and Meigs, James B and McKeown, Nicola M and Nettleton, Jennifer A} } @article {5848, title = {Long-chain monounsaturated Fatty acids and incidence of congestive heart failure in 2 prospective cohorts.}, journal = {Circulation}, volume = {127}, year = {2013}, month = {2013 Apr 09}, pages = {1512-21, 1521e1-18}, chapter = {1512}, abstract = {

BACKGROUND: Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown.

METHODS AND RESULTS: We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2{\textpm}5.2 years) in the Cardiovascular Health Study (CHS; 1992-2006) and 3577 middle-aged adults (mean age, 54.1{\textpm}5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987-2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003-2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95\% confidence interval, 1.02-1.76) and 1.57 (95\% confidence interval, 1.11-2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95\% confidence interval, 1.23-2.50) and 1.92 (95\% confidence interval, 1.22-3.03) for 24:1, respectively (P for trend <=0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard.

CONCLUSIONS: Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.

}, keywords = {Aged, Aged, 80 and over, Cross-Sectional Studies, Dietary Fats, Fatty Acids, Monounsaturated, Feeding Behavior, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Nutrition Surveys, Prospective Studies, Risk Factors, Stroke}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.001197}, author = {Imamura, Fumiaki and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Steffen, Lyn M and Folsom, Aaron R and Siscovick, David S and Mozaffarian, Dariush} } @article {6211, title = {Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults.}, journal = {Cardiol Res Pract}, volume = {2013}, year = {2013}, month = {2013}, pages = {181054}, abstract = {

Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95\% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95\% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95\% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

}, issn = {2090-8016}, doi = {10.1155/2013/181054}, author = {Djouss{\'e}, Luc and Maziarz, Marlena and Biggs, Mary L and Ix, Joachim H and Zieman, Susan J and Kizer, Jorge R and Lemaitre, Rozenn N and Mozaffarian, Dariush and Tracy, Russell P and Mukamal, Kenneth J and Siscovick, David S and Sotoodehnia, Nona} } @article {6064, title = {Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 Sep 01}, pages = {964-9}, abstract = {

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12\% (95\% confidence interval, 6\%-19\%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95\% confidence interval, 1.09-1.23]).

CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Fatty Acids, Nonesterified, Female, Heart Failure, Humans, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Multivariate Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Time Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.113.000521}, author = {Djouss{\'e}, Luc and Benkeser, David and Arnold, Alice and Kizer, Jorge R and Zieman, Susan J and Lemaitre, Rozenn N and Tracy, Russell P and Gottdiener, John S and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Ix, Joachim H} } @article {6079, title = {Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.}, journal = {Ann Intern Med}, volume = {158}, year = {2013}, month = {2013 Apr 02}, pages = {515-25}, abstract = {

BACKGROUND: Long-chain ω-3 polyunsaturated fatty acids (ω3-PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention.

OBJECTIVE: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PARTICIPANTS: 2692 U.S. adults aged 74 years ({\textpm}5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline.

MEASUREMENTS: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed.

RESULTS: During 30 829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95\% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than noncardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile.

LIMITATION: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding.

CONCLUSION: Higher circulating individual and total ω3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults.

PRIMARY FUNDING SOURCE: National Institutes of Health.

}, keywords = {Aged, Biomarkers, Cause of Death, Coronary Disease, Diet Records, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Feeding Behavior, Female, Humans, Male, Prospective Studies, Risk Assessment, Stroke}, issn = {1539-3704}, doi = {10.7326/0003-4819-158-7-201304020-00003}, author = {Mozaffarian, Dariush and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Huang, Hongyan and Sacks, Frank M and Rimm, Eric B and Wang, Molin and Siscovick, David S} } @article {6613, title = {Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {130}, year = {2014}, month = {2014 Oct 7}, pages = {1245-53}, abstract = {

BACKGROUND: Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.

METHODS AND RESULTS: Among 2792 participants(aged >=65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95\% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95\% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.

CONCLUSIONS: High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

}, keywords = {Aged, Arachidonic Acid, Biomarkers, Cohort Studies, Coronary Disease, Fatty Acids, Omega-3, Fatty Acids, Omega-6, Fatty Acids, Unsaturated, Female, Follow-Up Studies, Humans, Linoleic Acid, Male, Prospective Studies, Regression Analysis, Risk Factors, Stroke, Survival Rate, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.114.011590}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Psaty, Bruce M and Siscovick, David S and Mozaffarian, Dariush} } @article {6570, title = {A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.}, journal = {J Cardiovasc Electrophysiol}, volume = {25}, year = {2014}, month = {2014 Nov}, pages = {1150-7}, abstract = {

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2{\texttimes}10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 {\texttimes} 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Female, Genetic Variation, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Prospective Studies, Risk Factors, Single-Blind Method}, issn = {1540-8167}, doi = {10.1111/jce.12483}, author = {Ilkhanoff, Leonard and Arking, Dan E and Lemaitre, Rozenn N and Alonso, Alvaro and Chen, Lin Y and Durda, Peter and Hesselson, Stephanie E and Kerr, Kathleen F and Magnani, Jared W and Marcus, Gregory M and Schnabel, Renate B and Smith, J Gustav and Soliman, Elsayed Z and Reiner, Alexander P and Sotoodehnia, Nona} } @article {6325, title = {Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.}, journal = {Heart Rhythm}, volume = {11}, year = {2014}, month = {2014 Mar}, pages = {471-7}, abstract = {

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36\%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13\% lower SCA risk (95\% confidence interval -21\% to -5\%) in the discovery phase and 9\% lower SCA risk (95\% confidence interval -16\% to -1\%) in the replication phase.

CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

}, keywords = {1-Acylglycerophosphocholine O-Acyltransferase, Aged, Algorithms, Alleles, Case-Control Studies, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2014.01.008}, author = {Lemaitre, Rozenn N and Johnson, Catherine O and Hesselson, Stephanie and Sotoodehnia, Nona and Sotoodhenia, Nona and McKnight, Barbara and Sitlani, Colleen M and Rea, Thomas D and King, Irena B and Kwok, Pui-Yan and Mak, Angel and Li, Guo and Brody, Jennifer and Larson, Eric and Mozaffarian, Dariush and Psaty, Bruce M and Huertas-Vazquez, Adriana and Tardif, Jean-Claude and Albert, Christine M and Lyytik{\"a}inen, Leo-Pekka and Arking, Dan E and K{\"a}{\"a}b, Stefan and Huikuri, Heikki V and Krijthe, Bouwe P and Eijgelsheim, Mark and Wang, Ying A and Reinier, Kyndaron and Lehtim{\"a}ki, Terho and Pulit, Sara L and Brugada, Ramon and M{\"u}ller-Nurasyid, Martina and Newton-Cheh, Chris H and Karhunen, Pekka J and Stricker, Bruno H and Goyette, Philippe and Rotter, Jerome I and Chugh, Sumeet S and Chakravarti, Aravinda and Jouven, Xavier and Siscovick, David S} } @article {6938, title = {FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Dec 20}, pages = {6961-72}, abstract = {

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 {\texttimes} 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 {\texttimes} 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] \%, P = 2.4 {\texttimes} 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] \%, P = 0.004). The associations with protein (P = 7.5 {\texttimes} 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

}, keywords = {Adult, African Americans, Aged, Alleles, Asian Continental Ancestry Group, Body Mass Index, Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Female, Gene Frequency, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddu411}, author = {Qi, Qibin and Kilpel{\"a}inen, Tuomas O and Downer, Mary K and Tanaka, Toshiko and Smith, Caren E and Sluijs, Ivonne and Sonestedt, Emily and Chu, Audrey Y and Renstrom, Frida and Lin, Xiaochen and {\"A}ngquist, Lars H and Huang, Jinyan and Liu, Zhonghua and Li, Yanping and Asif Ali, Muhammad and Xu, Min and Ahluwalia, Tarunveer Singh and Boer, Jolanda M A and Chen, Peng and Daimon, Makoto and Eriksson, Johan and Perola, Markus and Friedlander, Yechiel and Gao, Yu-Tang and Heppe, Denise H M and Holloway, John W and Houston, Denise K and Kanoni, Stavroula and Kim, Yu-Mi and Laaksonen, Maarit A and J{\"a}{\"a}skel{\"a}inen, Tiina and Lee, Nanette R and Lehtim{\"a}ki, Terho and Lemaitre, Rozenn N and Lu, Wei and Luben, Robert N and Manichaikul, Ani and M{\"a}nnist{\"o}, Satu and Marques-Vidal, Pedro and Monda, Keri L and Ngwa, Julius S and Perusse, Louis and van Rooij, Frank J A and Xiang, Yong-Bing and Wen, Wanqing and Wojczynski, Mary K and Zhu, Jingwen and Borecki, Ingrid B and Bouchard, Claude and Cai, Qiuyin and Cooper, Cyrus and Dedoussis, George V and Deloukas, Panos and Ferrucci, Luigi and Forouhi, Nita G and Hansen, Torben and Christiansen, Lene and Hofman, Albert and Johansson, Ingegerd and J{\o}rgensen, Torben and Karasawa, Shigeru and Khaw, Kay-Tee and Kim, Mi-Kyung and Kristiansson, Kati and Li, Huaixing and Lin, Xu and Liu, Yongmei and Lohman, Kurt K and Long, Jirong and Mikkil{\"a}, Vera and Mozaffarian, Dariush and North, Kari and Pedersen, Oluf and Raitakari, Olli and Rissanen, Harri and Tuomilehto, Jaakko and van der Schouw, Yvonne T and Uitterlinden, Andr{\'e} G and Zillikens, M Carola and Franco, Oscar H and Shyong Tai, E and Ou Shu, Xiao and Siscovick, David S and Toft, Ulla and Verschuren, W M Monique and Vollenweider, Peter and Wareham, Nicholas J and Witteman, Jacqueline C M and Zheng, Wei and Ridker, Paul M and Kang, Jae H and Liang, Liming and Jensen, Majken K and Curhan, Gary C and Pasquale, Louis R and Hunter, David J and Mohlke, Karen L and Uusitupa, Matti and Cupples, L Adrienne and Rankinen, Tuomo and Orho-Melander, Marju and Wang, Tao and Chasman, Daniel I and Franks, Paul W and S{\o}rensen, Thorkild I A and Hu, Frank B and Loos, Ruth J F and Nettleton, Jennifer A and Qi, Lu} } @article {6567, title = {Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {321-331}, abstract = {

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55\% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1{\texttimes}10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2{\texttimes}10(-15), 5.0{\texttimes}10(-11), 7.6{\texttimes}10(-65), and 2.4{\texttimes}10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1{\texttimes}10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3{\texttimes}10(-72), 2.6{\texttimes}10(-151), and 6.3{\texttimes}10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 6, Fatty Acid Desaturases, Fatty Acids, Omega-6, Female, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000208}, author = {Guan, Weihua and Steffen, Brian T and Lemaitre, Rozenn N and Wu, Jason H Y and Tanaka, Toshiko and Manichaikul, Ani and Foy, Millennia and Rich, Stephen S and Wang, Lu and Nettleton, Jennifer A and Tang, Weihong and Gu, Xiangjun and Bandinelli, Stafania and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Siscovick, David and Djouss{\'e}, Luc and Chen, Yii-Der Ida and Ferrucci, Luigi and Fornage, Myriam and Mozafarrian, Dariush and Tsai, Michael Y and Steffen, Lyn M} } @article {6562, title = {Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study.}, journal = {Br J Nutr}, volume = {112}, year = {2014}, month = {2014 Oct 14}, pages = {1206-13}, abstract = {

Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18~:~3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged >=~65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0{\textperiodcentered}73 (95~\% CI 0{\textperiodcentered}61, 0{\textperiodcentered}88) and 0{\textperiodcentered}64 (95~\% CI 0{\textperiodcentered}52, 0{\textperiodcentered}80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.

}, keywords = {Aged, alpha-Linolenic Acid, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Diet, Female, Humans, Male, Mortality, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1475-2662}, doi = {10.1017/S0007114514001925}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Sitlani, Colleen and Psaty, Bruce M and Rimm, Eric B and Song, Xiaoling and McKnight, Barbara and Spiegelman, Donna and King, Irena B and Lemaitre, Rozenn N} } @article {6397, title = {Plasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Jun 26}, pages = {e000889}, abstract = {

BACKGROUND: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.

METHODS AND RESULTS: The study population included 2899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long-chain saturated fatty acids-palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)-with incident AF. During a median of 11.2 years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95\% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95\% CI) for AF in the top and bottom quartiles were 0.76 (95\% CI: 0.61, 0.95) for 18:0; 0.78 (95\% CI: 0.63, 0.97) for 20:0; 0.62 (95\% CI: 0.50, 0.78) for 22:0; and 0.68 (95\% CI: 0.55, 0.85) for 24:0.

CONCLUSIONS: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Eicosanoic Acids, Fatty Acids, Female, Humans, Longitudinal Studies, Male, Palmitic Acid, Phospholipids, Proportional Hazards Models, Prospective Studies, Risk Factors, Stearic Acids, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.114.000889}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and Djouss{\'e}, Luc and Heckbert, Susan R and King, Irena B and McKnight, Barbara and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Wallace, Erin R and Lemaitre, Rozenn N} } @article {6609, title = {Plasma phospholipid trans-fatty acids levels, cardiovascular diseases, and total mortality: the cardiovascular health study.}, journal = {J Am Heart Assoc}, volume = {3}, year = {2014}, month = {2014 Aug}, abstract = {

BACKGROUND: While self-reported trans-fatty acid (TFA) consumption is linked to coronary heart disease (CHD), relationships between objective biomarkers of TFA subtypes (t-16:1n9, total t-18:1, and cis/trans-(c/t-), t/c- and t/t-18:2) and cardiovascular disease (CVD) or total mortality are not well established.

METHODS AND RESULTS: We evaluated 2742 adults in the Cardiovascular Health Study, aged 74{\textpm}5 years and free of prevalent CVD, with plasma phospholipid TFA measures in 1992. Incident fatal and nonfatal CHD events, CVD and non-CVD mortality, and total mortality were centrally adjudicated through 2010. Risks were assessed using Cox proportional hazards. During 31 494 person-years, 1735 total deaths and 639 total CHD events occurred. In the multivariate model including mutual adjustment for the 5 TFA subtypes, circulating t/t-18:2 was associated with higher total mortality (extreme quintile hazard ratio (HR)=1.23, 95\% CI=1.04 to 1.44, P-trend=0.01), CVD mortality (HR=1.40, 95\% CI=1.05 to 1.86, P-trend=0.02), and total CHD (HR=1.39, 95\% CI=1.06 to 1.83, P-trend=0.01). t/c-18:2 was positively related to total mortality (HR=1.19, P-trend=0.05), total CHD (HR=1.67, P-trend=0.002), and nonfatal CHD (HR=2.06, P-trend=0.002) after mutual adjustment; these associations were insignificant without mutual adjustment. Neither t-16:1n9 nor t-18:1 was significantly associated with total mortality or CVD, nor was c/t-18:2 if we excluded early cases.

CONCLUSIONS: Among circulating TFAs, t/t-18:2 was most adversely associated with total mortality, mainly due to the increased risk of CVD. t/c-18:2 was also positively associated with total mortality and CHD, but only after adjustment for other TFAs. These results highlight the need for further investigation of dietary sources, nondietary determinants, and health effects of specific TFA subtypes, especially t-18:2 isomers.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cohort Studies, Dietary Fats, Female, Follow-Up Studies, Humans, Incidence, Male, Mortality, Phospholipids, Prognosis, Proportional Hazards Models, Prospective Studies, Trans Fatty Acids}, issn = {2047-9980}, doi = {10.1161/JAHA.114.000914}, author = {Wang, Qianyi and Imamura, Fumiaki and Lemaitre, Rozenn N and Rimm, Eric B and Wang, Molin and King, Irena B and Song, Xiaoling and Siscovick, David and Mozaffarian, Dariush} } @article {6664, title = {Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {38}, year = {2015}, month = {2015 Jun}, pages = {1099-107}, abstract = {

OBJECTIVE: To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.

RESEARCH DESIGN AND METHODS: In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 {\textpm} 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.

RESULTS: In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95\% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00-1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.

CONCLUSIONS: Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.

}, keywords = {Aged, Biomarkers, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Dietary Fats, Unsaturated, Epidemiologic Methods, Female, Food Habits, Humans, Male, Phospholipids, Trans Fatty Acids}, issn = {1935-5548}, doi = {10.2337/dc14-2101}, author = {Wang, Qianyi and Imamura, Fumiaki and Ma, Wenjie and Wang, Molin and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Mukamal, Kenneth J and Djouss{\'e}, Luc and Siscovick, David S and Mozaffarian, Dariush} } @article {6844, title = {Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.}, journal = {Am J Clin Nutr}, volume = {102}, year = {2015}, month = {2015 Nov}, pages = {1266-78}, abstract = {

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95\% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95\% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95\% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

}, keywords = {Blood Glucose, Cohort Studies, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hyperglycemia, Hyperinsulinism, Insulin, Insulin Resistance, Insulin-Secreting Cells, Meat, Meat Products, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101238}, author = {Fretts, Amanda M and Follis, Jack L and Nettleton, Jennifer A and Lemaitre, Rozenn N and Ngwa, Julius S and Wojczynski, Mary K and Kalafati, Ioanna Panagiota and Varga, Tibor V and Frazier-Wood, Alexis C and Houston, Denise K and Lahti, Jari and Ericson, Ulrika and van den Hooven, Edith H and Mikkil{\"a}, Vera and Kiefte-de Jong, Jessica C and Mozaffarian, Dariush and Rice, Kenneth and Renstrom, Frida and North, Kari E and McKeown, Nicola M and Feitosa, Mary F and Kanoni, Stavroula and Smith, Caren E and Garcia, Melissa E and Tiainen, Anna-Maija and Sonestedt, Emily and Manichaikul, Ani and van Rooij, Frank J A and Dimitriou, Maria and Raitakari, Olli and Pankow, James S and Djouss{\'e}, Luc and Province, Michael A and Hu, Frank B and Lai, Chao-Qiang and Keller, Margaux F and Per{\"a}l{\"a}, Mia-Maria and Rotter, Jerome I and Hofman, Albert and Graff, Misa and K{\"a}h{\"o}nen, Mika and Mukamal, Kenneth and Johansson, Ingegerd and Ordovas, Jose M and Liu, Yongmei and M{\"a}nnist{\"o}, Satu and Uitterlinden, Andr{\'e} G and Deloukas, Panos and Sepp{\"a}l{\"a}, Ilkka and Psaty, Bruce M and Cupples, L Adrienne and Borecki, Ingrid B and Franks, Paul W and Arnett, Donna K and Nalls, Mike A and Eriksson, Johan G and Orho-Melander, Marju and Franco, Oscar H and Lehtim{\"a}ki, Terho and Dedoussis, George V and Meigs, James B and Siscovick, David S} } @article {6687, title = {Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.}, journal = {Mol Nutr Food Res}, volume = {59}, year = {2015}, month = {2015 Jul}, pages = {1373-83}, abstract = {

SCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.

METHODS AND RESULTS: We conducted meta-analyses (N = 11~668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.

CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.

}, keywords = {Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1613-4133}, doi = {10.1002/mnfr.201400734}, author = {Smith, Caren E and Follis, Jack L and Nettleton, Jennifer A and Foy, Millennia and Wu, Jason H Y and Ma, Yiyi and Tanaka, Toshiko and Manichakul, Ani W and Wu, Hongyu and Chu, Audrey Y and Steffen, Lyn M and Fornage, Myriam and Mozaffarian, Dariush and Kabagambe, Edmond K and Ferruci, Luigi and Chen, Yii-Der Ida and Rich, Stephen S and Djouss{\'e}, Luc and Ridker, Paul M and Tang, Weihong and McKnight, Barbara and Tsai, Michael Y and Bandinelli, Stefania and Rotter, Jerome I and Hu, Frank B and Chasman, Daniel I and Psaty, Bruce M and Arnett, Donna K and King, Irena B and Sun, Qi and Wang, Lu and Lumley, Thomas and Chiuve, Stephanie E and Siscovick, David S and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {6802, title = {Gene {\texttimes} dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Aug 15}, pages = {4728-38}, abstract = {

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR~and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

}, keywords = {Adult, Body Mass Index, Case-Control Studies, Diet, Western, Epistasis, Genetic, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Obesity, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddv186}, author = {Nettleton, Jennifer A and Follis, Jack L and Ngwa, Julius S and Smith, Caren E and Ahmad, Shafqat and Tanaka, Toshiko and Wojczynski, Mary K and Voortman, Trudy and Lemaitre, Rozenn N and Kristiansson, Kati and Nuotio, Marja-Liisa and Houston, Denise K and Per{\"a}l{\"a}, Mia-Maria and Qi, Qibin and Sonestedt, Emily and Manichaikul, Ani and Kanoni, Stavroula and Ganna, Andrea and Mikkil{\"a}, Vera and North, Kari E and Siscovick, David S and Harald, Kennet and McKeown, Nicola M and Johansson, Ingegerd and Rissanen, Harri and Liu, Yongmei and Lahti, Jari and Hu, Frank B and Bandinelli, Stefania and Rukh, Gull and Rich, Stephen and Booij, Lisanne and Dmitriou, Maria and Ax, Erika and Raitakari, Olli and Mukamal, Kenneth and M{\"a}nnist{\"o}, Satu and Hallmans, G{\"o}ran and Jula, Antti and Ericson, Ulrika and Jacobs, David R and van Rooij, Frank J A and Deloukas, Panos and Sjogren, Per and K{\"a}h{\"o}nen, Mika and Djouss{\'e}, Luc and Perola, Markus and Barroso, In{\^e}s and Hofman, Albert and Stirrups, Kathleen and Viikari, Jorma and Uitterlinden, Andr{\'e} G and Kalafati, Ioanna P and Franco, Oscar H and Mozaffarian, Dariush and Salomaa, Veikko and Borecki, Ingrid B and Knekt, Paul and Kritchevsky, Stephen B and Eriksson, Johan G and Dedoussis, George V and Qi, Lu and Ferrucci, Luigi and Orho-Melander, Marju and Zillikens, M Carola and Ingelsson, Erik and Lehtim{\"a}ki, Terho and Renstrom, Frida and Cupples, L Adrienne and Loos, Ruth J F and Franks, Paul W} } @article {6615, title = {Genetic loci associated with circulating levels of very long-chain saturated fatty acids.}, journal = {J Lipid Res}, volume = {56}, year = {2015}, month = {2015 Jan}, pages = {176-84}, abstract = {

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 {\texttimes} 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 {\texttimes} 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 {\texttimes} 10(-26)) and lignoceric acid (P = 3.20 {\texttimes} 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

}, keywords = {Cohort Studies, Fatty Acids, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans}, issn = {1539-7262}, doi = {10.1194/jlr.M052456}, author = {Lemaitre, Rozenn N and King, Irena B and Kabagambe, Edmond K and Wu, Jason H Y and McKnight, Barbara and Manichaikul, Ani and Guan, Weihua and Sun, Qi and Chasman, Daniel I and Foy, Millennia and Wang, Lu and Zhu, Jingwen and Siscovick, David S and Tsai, Michael Y and Arnett, Donna K and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Yii-der I and Tang, Weihong and Weng, Lu-Chen and Wu, Hongyu and Jensen, Majken K and Chu, Audrey Y and Jacobs, David R and Rich, Stephen S and Mozaffarian, Dariush and Steffen, Lyn and Rimm, Eric B and Hu, Frank B and Ridker, Paul M and Fornage, Myriam and Friedlander, Yechiel} } @article {6685, title = {Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Feb}, pages = {398-406}, abstract = {

BACKGROUND: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.

OBJECTIVE: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.

DESIGN: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.

RESULTS: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 {\texttimes} 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 {\texttimes} 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 {\texttimes} 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86\%), with similar reductions in Hispanic Americans and Chinese Americans.

CONCLUSIONS: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

}, keywords = {African Americans, Arachidonic Acid, Asian Americans, Biomarkers, European Continental Ancestry Group, Fatty Acids, Omega-6, Gene Frequency, Genetic Association Studies, Genetic Loci, Genotyping Techniques, Humans, Phospholipids, Polymorphism, Single Nucleotide, Trans Fatty Acids}, issn = {1938-3207}, doi = {10.3945/ajcn.114.094557}, author = {Mozaffarian, Dariush and Kabagambe, Edmond K and Johnson, Catherine O and Lemaitre, Rozenn N and Manichaikul, Ani and Sun, Qi and Foy, Millennia and Wang, Lu and Wiener, Howard and Irvin, Marguerite R and Rich, Stephen S and Wu, Hongyu and Jensen, Majken K and Chasman, Daniel I and Chu, Audrey Y and Fornage, Myriam and Steffen, Lyn and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Ida Y-D and Wu, Jason H Y and Siscovick, David S and Ridker, Paul M and Tsai, Michael Y and Rimm, Eric B and Hu, Frank B and Arnett, Donna K} } @article {6614, title = {Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {135-43}, abstract = {

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β {\textpm} SE = 0.16 {\textpm} 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 {\textpm} 0.06\%, P = 0.03; women: 0.10 {\textpm} 0.05\%, P = 0.04) and with lower carbohydrate (-0.31 {\textpm} 0.12\%, P < 0.01), higher total fat (0.18 {\textpm} 0.09\%, P = 0.05), and higher PUFA (0.05 {\textpm} 0.02\%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

}, keywords = {Adult, Body Mass Index, CLOCK Proteins, Cohort Studies, Cross-Sectional Studies, Diet, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Fatty Acids, Unsaturated, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Sleep, Young Adult}, issn = {1938-3207}, doi = {10.3945/ajcn.114.095026}, author = {Dashti, Hassan S and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Cade, Brian E and Gottlieb, Daniel J and Hruby, Adela and Jacques, Paul F and Lamon-Fava, Stefania and Richardson, Kris and Saxena, Richa and Scheer, Frank A J L and Kovanen, Leena and Bartz, Traci M and Per{\"a}l{\"a}, Mia-Maria and Jonsson, Anna and Frazier-Wood, Alexis C and Kalafati, Ioanna-Panagiota and Mikkil{\"a}, Vera and Partonen, Timo and Lemaitre, Rozenn N and Lahti, Jari and Hernandez, Dena G and Toft, Ulla and Johnson, W Craig and Kanoni, Stavroula and Raitakari, Olli T and Perola, Markus and Psaty, Bruce M and Ferrucci, Luigi and Grarup, Niels and Highland, Heather M and Rallidis, Loukianos and K{\"a}h{\"o}nen, Mika and Havulinna, Aki S and Siscovick, David S and R{\"a}ikk{\"o}nen, Katri and J{\o}rgensen, Torben and Rotter, Jerome I and Deloukas, Panos and Viikari, Jorma S A and Mozaffarian, Dariush and Linneberg, Allan and Sepp{\"a}l{\"a}, Ilkka and Hansen, Torben and Salomaa, Veikko and Gharib, Sina A and Eriksson, Johan G and Bandinelli, Stefania and Pedersen, Oluf and Rich, Stephen S and Dedoussis, George and Lehtim{\"a}ki, Terho and Ordovas, Jose M} } @article {6663, title = {Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 May}, pages = {1047-54}, abstract = {

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47\% lower risk of diabetes (95\% CI: 23\%, 63\%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33\% (95\% CI: 6\%, 53\%; P-trend: 0.02) and 37\% (95\% CI: 11\%, 55\%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32\% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cross-Sectional Studies, Diabetes Mellitus, Diet, Eicosanoic Acids, Fatty Acids, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Observational Studies as Topic, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101857}, author = {Lemaitre, Rozenn N and Fretts, Amanda M and Sitlani, Colleen M and Biggs, Mary L and Mukamal, Kenneth and King, Irena B and Song, Xiaoling and Djouss{\'e}, Luc and Siscovick, David S and McKnight, Barbara and Sotoodehnia, Nona and Kizer, Jorge R and Mozaffarian, Dariush} } @article {6616, title = {Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {153-63}, abstract = {

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95\% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95\% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95\% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

}, keywords = {Aged, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Incidence, Lipogenesis, Liver, Male, Palmitic Acid, Phospholipids, Prevalence, Proportional Hazards Models, Risk Factors, Stearic Acids, United States, Up-Regulation}, issn = {1938-3207}, doi = {10.3945/ajcn.114.092601}, author = {Ma, Wenjie and Wu, Jason H Y and Wang, Qianyi and Lemaitre, Rozenn N and Mukamal, Kenneth J and Djouss{\'e}, Luc and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Kizer, Jorge R and Siscovick, David S and Mozaffarian, Dariush} } @article {6929, title = {Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length.}, journal = {J Nutr}, volume = {146}, year = {2016}, month = {2016 Feb}, pages = {298-305}, abstract = {

BACKGROUND: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality.

OBJECTIVE: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged >=65 y who were followed from 1992 through 2011.

METHODS: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models.

RESULTS: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95\% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality.

CONCLUSIONS: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Diet, Dietary Fats, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Mortality, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Stearic Acids}, issn = {1541-6100}, doi = {10.3945/jn.115.222117}, author = {Fretts, Amanda M and Mozaffarian, Dariush and Siscovick, David S and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Rimm, Eric B and Sitlani, Colleen and Sacks, Frank M and Song, Xiaoling and Sotoodehnia, Nona and Spiegelman, Donna and Lemaitre, Rozenn N} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {7346, title = {Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations.}, journal = {J Lipid Res}, year = {2017}, month = {2017 Mar 15}, abstract = {

Monounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 15,000 participants of Chinese- and European-ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor)>=8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor)>=61619;6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99\% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.

}, issn = {1539-7262}, doi = {10.1194/jlr.P071860}, author = {Hu, Yao and Tanaka, Toshiko and Zhu, Jingwen and Guan, Weihua and Wu, Jason H Y and Psaty, Bruce M and McKnight, Barbara and King, Irena B and Sun, Qi and Richard, Melissa and Manichaikul, Ani and Frazier-Wood, Alexis C and Kabagambe, Edmond K and Hopkins, Paul N and Ordovas, Jose M and Ferrucci, Luigi and Bandinelli, Stefania and Arnett, Donna K and Chen, Yii-der I and Liang, Shuang and Siscovick, David S and Tsai, Michael Y and Rich, Stephen S and Fornage, Myriam and Hu, Frank B and Rimm, Eric B and Jensen, Majken K and Lemaitre, Rozenn N and Mozaffarian, Dariush and Steffen, Lyn M and Morris, Andrew P and Li, Huaixing and Lin, Xu} } @article {7588, title = {Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.}, journal = {Mol Nutr Food Res}, year = {2017}, month = {2017 Sep 21}, abstract = {

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3{\textquoteright} of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 {\texttimes} 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

}, issn = {1613-4133}, doi = {10.1002/mnfr.201700347}, author = {Smith, Caren E and Follis, Jack L and Dashti, Hassan S and Tanaka, Toshiko and Graff, Mariaelisa and Fretts, Amanda M and Kilpel{\"a}inen, Tuomas O and Wojczynski, Mary K and Richardson, Kris and Nalls, Mike A and Schulz, Christina-Alexandra and Liu, Yongmei and Frazier-Wood, Alexis C and van Eekelen, Esther and Wang, Carol and de Vries, Paul S and Mikkil{\"a}, Vera and Rohde, Rebecca and Psaty, Bruce M and Hansen, Torben and Feitosa, Mary F and Lai, Chao-Qiang and Houston, Denise K and Ferruci, Luigi and Ericson, Ulrika and Wang, Zhe and de Mutsert, Ren{\'e}e and Oddy, Wendy H and de Jonge, Ester A L and Sepp{\"a}l{\"a}, Ilkka and Justice, Anne E and Lemaitre, Rozenn N and S{\o}rensen, Thorkild I A and Province, Michael A and Parnell, Laurence D and Garcia, Melissa E and Bandinelli, Stefania and Orho-Melander, Marju and Rich, Stephen S and Rosendaal, Frits R and Pennell, Craig E and Kiefte-de Jong, Jessica C and K{\"a}h{\"o}nen, Mika and Young, Kristin L and Pedersen, Oluf and Aslibekyan, Stella and Rotter, Jerome I and Mook-Kanamori, Dennis O and Zillikens, M Carola and Raitakari, Olli T and North, Kari E and Overvad, Kim and Arnett, Donna K and Hofman, Albert and Lehtim{\"a}ki, Terho and Tj{\o}nneland, Anne and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Franco, Oscar H and German, J Bruce and Siscovick, David S and Cupples, L Adrienne and Ordovas, Jose M} } @article {7490, title = {Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.}, journal = {Stroke}, volume = {48}, year = {2017}, month = {2017 Oct}, pages = {2678-2685}, abstract = {

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.

METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses{\textquoteright} Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis.

RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95\% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95\% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95\% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95\% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95\% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results.

CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

}, keywords = {Adult, Aged, Aged, 80 and over, Biomarkers, Brain Ischemia, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Fatty Acids, Omega-3, Female, Follow-Up Studies, Humans, Incidence, Intracranial Arteriosclerosis, Intracranial Embolism, Intracranial Thrombosis, Male, Middle Aged, Prospective Studies, Random Allocation, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.117.018235}, author = {Saber, Hamidreza and Yakoob, Mohammad Yawar and Shi, Peilin and Longstreth, W T and Lemaitre, Rozenn N and Siscovick, David and Rexrode, Kathryn M and Willett, Walter C and Mozaffarian, Dariush} } @article {7919, title = {Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {7}, year = {2018}, month = {2018 Nov 06}, pages = {e010019}, abstract = {

Background Circulating very-long-chain saturated fatty acids ( VLSFAs ) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure ( HF ) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF ( P trend<=0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95\% confidence interval, 0.55-0.81) for 24:0, 0.72 (95\% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95\% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005133.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010019}, author = {Lemaitre, Rozenn N and McKnight, Barbara and Sotoodehnia, Nona and Fretts, Amanda M and Qureshi, Waqas T and Song, Xiaoling and King, Irena B and Sitlani, Colleen M and Siscovick, David S and Psaty, Bruce M and Mozaffarian, Dariush} } @article {7778, title = {A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.}, journal = {Eur Heart J}, year = {2018}, month = {2018 Aug 28}, abstract = {

Aims: Sudden cardiac arrest (SCA) accounts for 10\% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25~989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehy474}, author = {Ashar, Foram N and Mitchell, Rebecca N and Albert, Christine M and Newton-Cheh, Christopher and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Moes, Anna and Meitinger, Thomas and Mak, Angel and Huikuri, Heikki and Junttila, M Juhani and Goyette, Philippe and Pulit, Sara L and Pazoki, Raha and Tanck, Michael W and Blom, Marieke T and Zhao, XiaoQing and Havulinna, Aki S and Jabbari, Reza and Glinge, Charlotte and Tragante, Vinicius and Escher, Stefan A and Chakravarti, Aravinda and Ehret, Georg and Coresh, Josef and Li, Man and Prineas, Ronald J and Franco, Oscar H and Kwok, Pui-Yan and Lumley, Thomas and Dumas, Florence and McKnight, Barbara and Rotter, Jerome I and Lemaitre, Rozenn N and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Hwang, Shih-Jen and Tardif, Jean-Claude and VanDenburgh, Martin and Uitterlinden, Andr{\'e} G and Hofman, Albert and Stricker, Bruno H C and de Bakker, Paul I W and Franks, Paul W and Jansson, Jan-H{\r a}kan and Asselbergs, Folkert W and Halushka, Marc K and Maleszewski, Joseph J and Tfelt-Hansen, Jacob and Engstr{\o}m, Thomas and Salomaa, Veikko and Virmani, Renu and Kolodgie, Frank and Wilde, Arthur A M and Tan, Hanno L and Bezzina, Connie R and Eijgelsheim, Mark and Rioux, John D and Jouven, Xavier and K{\"a}{\"a}b, Stefan and Psaty, Bruce M and Siscovick, David S and Arking, Dan E and Sotoodehnia, Nona} } @article {8041, title = {Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.}, journal = {PLoS Med}, volume = {15}, year = {2018}, month = {2018 10}, pages = {e1002670}, abstract = {

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95\% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

}, keywords = {Aged, Australia, Biomarkers, Dairy Products, Diabetes Mellitus, Type 2, Dietary Fats, Europe, Fatty Acids, Fatty Acids, Monounsaturated, Female, Humans, Incidence, Male, Middle Aged, Prospective Studies, Sex Factors, Taiwan, United States}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002670}, author = {Imamura, Fumiaki and Fretts, Amanda and Marklund, Matti and Ardisson Korat, Andres V and Yang, Wei-Sin and Lankinen, Maria and Qureshi, Waqas and Helmer, Catherine and Chen, Tzu-An and Wong, Kerry and Bassett, Julie K and Murphy, Rachel and Tintle, Nathan and Yu, Chaoyu Ian and Brouwer, Ingeborg A and Chien, Kuo-Liong and Frazier-Wood, Alexis C and Del Gobbo, Liana C and Djouss{\'e}, Luc and Geleijnse, Johanna M and Giles, Graham G and de Goede, Janette and Gudnason, Vilmundur and Harris, William S and Hodge, Allison and Hu, Frank and Koulman, Albert and Laakso, Markku and Lind, Lars and Lin, Hung-Ju and McKnight, Barbara and Rajaobelina, Kalina and Riserus, Ulf and Robinson, Jennifer G and Samieri, Cecilia and Siscovick, David S and Soedamah-Muthu, Sabita S and Sotoodehnia, Nona and Sun, Qi and Tsai, Michael Y and Uusitupa, Matti and Wagenknecht, Lynne E and Wareham, Nick J and Wu, Jason HY and Micha, Renata and Forouhi, Nita G and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {7791, title = {Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0196951}, abstract = {

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37{\texttimes}10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07{\texttimes}10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4{\texttimes}10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5{\texttimes}10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

}, keywords = {Fatty Acids, Genome-Wide Association Study, Humans, Introns, Lactase, Myosins, Polymorphism, Single Nucleotide, Sphingomyelins, Sphingosine N-Acyltransferase, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0196951}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Sun, Qi and King, Irena B and Wu, Jason H Y and Manichaikul, Ani and Rich, Stephen S and Tsai, Michael Y and Chen, Y D and Fornage, Myriam and Weihua, Guan and Aslibekyan, Stella and Irvin, Marguerite R and Kabagambe, Edmond K and Arnett, Donna K and Jensen, Majken K and McKnight, Barbara and Psaty, Bruce M and Steffen, Lyn M and Smith, Caren E and Riserus, Ulf and Lind, Lars and Hu, Frank B and Rimm, Eric B and Siscovick, David S and Mozaffarian, Dariush} } @article {7775, title = {Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.}, journal = {Br J Nutr}, year = {2018}, month = {2018 Sep 12}, pages = {1-12}, abstract = {

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1{\textperiodcentered}1 ml in EA (95 \% CI 0{\textperiodcentered}9, 1{\textperiodcentered}3; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}8 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}5; P<0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}06), and forced vital capacity (FVC) was higher by 1{\textperiodcentered}3 ml in EA (95 \% CI 1{\textperiodcentered}0, 1{\textperiodcentered}6; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}5 ml (95 \% CI 0{\textperiodcentered}8, 2{\textperiodcentered}3; P=0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}3) for current smokers and 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}2, 2{\textperiodcentered}1) for former smokers, compared with 0{\textperiodcentered}8 ml (95 \% CI 0{\textperiodcentered}4, 1{\textperiodcentered}2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

}, issn = {1475-2662}, doi = {10.1017/S0007114518002180}, author = {Xu, Jiayi and Bartz, Traci M and Chittoor, Geetha and Eiriksdottir, Gudny and Manichaikul, Ani W and Sun, Fangui and Terzikhan, Natalie and Zhou, Xia and Booth, Sarah L and Brusselle, Guy G and de Boer, Ian H and Fornage, Myriam and Frazier-Wood, Alexis C and Graff, Mariaelisa and Gudnason, Vilmundur and Harris, Tamara B and Hofman, Albert and Hou, Ruixue and Houston, Denise K and Jacobs, David R and Kritchevsky, Stephen B and Latourelle, Jeanne and Lemaitre, Rozenn N and Lutsey, Pamela L and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Pankow, James S and Psaty, Bruce M and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Smith, Lewis J and Stricker, Bruno H and Voruganti, V Saroja and Wang, Thomas J and Zillikens, M Carola and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Lahousse, Lies and London, Stephanie J and North, Kari E and Smith, Albert V and Steffen, Lyn M and Hancock, Dana B and Cassano, Patricia A} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {7776, title = {Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.}, journal = {Am J Respir Crit Care Med}, year = {2018}, month = {2018 Sep 10}, abstract = {

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4{\texttimes}10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80\%) was associated with lower FVC (P=2.1{\texttimes}10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1{\texttimes}10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

}, issn = {1535-4970}, doi = {10.1164/rccm.201802-0304OC}, author = {Xu, Jiayi and Gaddis, Nathan C and Bartz, Traci M and Hou, Ruixue and Manichaikul, Ani W and Pankratz, Nathan and Smith, Albert V and Sun, Fangui and Terzikhan, Natalie and Markunas, Christina A and Patchen, Bonnie K and Schu, Matthew and Beydoun, May A and Brusselle, Guy G and Eiriksdottir, Gudny and Zhou, Xia and Wood, Alexis C and Graff, Mariaelisa and Harris, Tamara B and Ikram, M Arfan and Jacobs, David R and Launer, Lenore J and Lemaitre, Rozenn N and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Psaty, Bruce M and Ramachandran, Vasan S and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Smith, Lewis J and Tiemeier, Henning and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and Voruganti, V Saroja and Xu, Hanfei and Zilh{\~a}o, Nuno R and Fornage, Myriam and Zillikens, M Carola and London, Stephanie J and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Gudnason, Vilmundur and Lahousse, Lies and North, Kari E and Steffen, Lyn M and Cassano, Patricia A and Hancock, Dana B} } @article {7918, title = {Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study.}, journal = {BMJ}, volume = {363}, year = {2018}, month = {2018 Oct 17}, pages = {k4067}, abstract = {

OBJECTIVE: To determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.

DESIGN: Prospective cohort study.

SETTING: Four communities in the United States (Cardiovascular Health Study) from 1992 to 2015.

PARTICIPANTS: 2622 adults with a mean (SD) age of 74.4 (4.8) and with successful healthy ageing at baseline in 1992-93.

EXPOSURE: Cumulative levels of plasma phospholipid n3-PUFAs were measured using gas chromatography in 1992-93, 1998-99, and 2005-06, expressed as percentage of total fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood.

MAIN OUTCOME MEASURE: Healthy ageing defined as survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Events were centrally adjudicated or determined from medical records and diagnostic tests.

RESULTS: Higher levels of long chain n3-PUFAs were associated with an 18\% lower risk (95\% confidence interval 7\% to 28\%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15\% (6\% to 23\%) and 16\% (6\% to 25\%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95\% confidence interval 0.83 to 1.02).

CONCLUSIONS: In older adults, a higher cumulative level of serially measured circulating n3-PUFAs from seafood (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid), eicosapentaenoic acid, and docosapentaenoic acid (but not docosahexaenoic acid from seafood or α-linolenic acid from plants) was associated with a higher likelihood of healthy ageing. These findings support guidelines for increased dietary consumption of n3-PUFAs in older adults.

}, issn = {1756-1833}, doi = {10.1136/bmj.k4067}, author = {Lai, Heidi Tm and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and McKnight, Barbara and Song, Xiaoling and King, Irena B and Chaves, Paulo Hm and Odden, Michelle C and Newman, Anne B and Siscovick, David S and Mozaffarian, Dariush} } @article {7790, title = {Serial measures of circulating biomarkers of dairy fat and total and cause-specific mortality in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, year = {2018}, month = {2018 Jul 11}, abstract = {

Background: Controversy has emerged about the benefits compared with harms of dairy fat, including concerns over long-term effects. Previous observational studies have assessed self-reported estimates of consumption or a single biomarker measure at baseline, which may lead to suboptimal estimation of true risk.

Objective: The aim of this study was to investigate prospective associations of serial measures of plasma phospholipid fatty acids pentadecanoic (15:0), heptadecanoic (17:0), and trans-palmitoleic (trans-16:1n-7) acids with total mortality, cause-specific mortality, and cardiovascular disease (CVD) risk among older adults.

Design: Among 2907 US adults aged >=65 y and free of CVD at baseline, circulating fatty acid concentrations were measured serially at baseline, 6 y, and 13 y. Deaths and CVD events were assessed and adjudicated centrally. Prospective associations were assessed by multivariate-adjusted Cox models incorporating time-dependent exposures and covariates.

Results: During 22 y of follow-up, 2428 deaths occurred, including 833 from CVD, 1595 from non-CVD causes, and 1301 incident CVD events. In multivariable models, circulating pentadecanoic, heptadecanoic, and trans-palmitoleic acids were not significantly associated with total mortality, with extreme-quintile HRs of 1.05 for pentadecanoic (95\% CI: 0.91, 1.22), 1.07 for heptadecanoic (95\% CI: 0.93, 1.23), and 1.05 for trans-palmitoleic (95\% CI: 0.91, 1.20) acids. Circulating heptadecanoic acid was associated with lower CVD mortality (extreme-quintile HR: 0.77; 95\% CI: 0.61, 0.98), especially stroke mortality, with a 42\% lower risk when comparing extreme quintiles of heptadecanoic acid concentrations (HR: 0.58; 95\% CI: 0.35, 0.97). In contrast, heptadecanoic acid was associated with a higher risk of non-CVD mortality (HR: 1.27; 95\% CI: 1.07, 1.52), which was not clearly related to any single subtype of non-CVD death. No significant associations of pentadecanoic, heptadecanoic, or trans-palmitoleic acids were seen for total incident CVD, coronary heart disease, or stroke.

Conclusions: Long-term exposure to circulating phospholipid pentadecanoic, heptadecanoic, or trans-palmitoleic acids was not significantly associated with total mortality or incident CVD among older adults. High circulating heptadecanoic acid was inversely associated with CVD and stroke mortality and potentially associated with higher risk of non-CVD death.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy117}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Song, Xiaoling and King, Irena B and Siscovick, David S and Mozaffarian, Dariush} } @article {7576, title = {Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.}, journal = {Diabetologia}, volume = {61}, year = {2018}, month = {2018 Feb}, pages = {317-330}, abstract = {

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β~{\textpm}~SE 0.014~{\textpm}~0.004 [mmol/l], p~=~1.5~{\texttimes}~10-3) and higher fasting insulin (0.030~{\textpm}~0.005 [log e pmol/l], p~=~2.0~{\texttimes}~10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030~{\textpm}~0.011 log e pmol/l, uncorrected p~=~0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses{\textquoteright} Health Study).

}, issn = {1432-0428}, doi = {10.1007/s00125-017-4475-0}, author = {McKeown, Nicola M and Dashti, Hassan S and Ma, Jiantao and Haslam, Danielle E and Kiefte-de Jong, Jessica C and Smith, Caren E and Tanaka, Toshiko and Graff, Mariaelisa and Lemaitre, Rozenn N and Rybin, Denis and Sonestedt, Emily and Frazier-Wood, Alexis C and Mook-Kanamori, Dennis O and Li, Yanping and Wang, Carol A and Leermakers, Elisabeth T M and Mikkil{\"a}, Vera and Young, Kristin L and Mukamal, Kenneth J and Cupples, L Adrienne and Schulz, Christina-Alexandra and Chen, Tzu-An and Li-Gao, Ruifang and Huang, Tao and Oddy, Wendy H and Raitakari, Olli and Rice, Kenneth and Meigs, James B and Ericson, Ulrika and Steffen, Lyn M and Rosendaal, Frits R and Hofman, Albert and K{\"a}h{\"o}nen, Mika and Psaty, Bruce M and Brunkwall, Louise and Uitterlinden, Andr{\'e} G and Viikari, Jorma and Siscovick, David S and Sepp{\"a}l{\"a}, Ilkka and North, Kari E and Mozaffarian, Dariush and Dupuis, Jos{\'e}e and Orho-Melander, Marju and Rich, Stephen S and de Mutsert, Ren{\'e}e and Qi, Lu and Pennell, Craig E and Franco, Oscar H and Lehtim{\"a}ki, Terho and Herman, Mark A} } @article {8047, title = {Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.}, journal = {Circulation}, volume = {139}, year = {2019}, month = {2019 May 21}, pages = {2422-2436}, abstract = {

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.

METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).

RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95\% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.

CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.038908}, author = {Marklund, Matti and Wu, Jason H Y and Imamura, Fumiaki and Del Gobbo, Liana C and Fretts, Amanda and de Goede, Janette and Shi, Peilin and Tintle, Nathan and Wennberg, Maria and Aslibekyan, Stella and Chen, Tzu-An and de Oliveira Otto, Marcia C and Hirakawa, Yoichiro and Eriksen, Helle H{\o}jmark and Kr{\"o}ger, Janine and Laguzzi, Federica and Lankinen, Maria and Murphy, Rachel A and Prem, Kiesha and Samieri, Cecilia and Virtanen, Jyrki and Wood, Alexis C and Wong, Kerry and Yang, Wei-Sin and Zhou, Xia and Baylin, Ana and Boer, Jolanda M A and Brouwer, Ingeborg A and Campos, Hannia and Chaves, Paulo H M and Chien, Kuo-Liong and de Faire, Ulf and Djouss{\'e}, Luc and Eiriksdottir, Gudny and El-Abbadi, Naglaa and Forouhi, Nita G and Michael Gaziano, J and Geleijnse, Johanna M and Gigante, Bruna and Giles, Graham and Guallar, Eliseo and Gudnason, Vilmundur and Harris, Tamara and Harris, William S and Helmer, Catherine and Hellenius, Mai-Lis and Hodge, Allison and Hu, Frank B and Jacques, Paul F and Jansson, Jan-H{\r a}kan and Kalsbeek, Anya and Khaw, Kay-Tee and Koh, Woon-Puay and Laakso, Markku and Leander, Karin and Lin, Hung-Ju and Lind, Lars and Luben, Robert and Luo, Juhua and McKnight, Barbara and Mursu, Jaakko and Ninomiya, Toshiharu and Overvad, Kim and Psaty, Bruce M and Rimm, Eric and Schulze, Matthias B and Siscovick, David and Skjelbo Nielsen, Michael and Smith, Albert V and Steffen, Brian T and Steffen, Lyn and Sun, Qi and Sundstr{\"o}m, Johan and Tsai, Michael Y and Tunstall-Pedoe, Hugh and Uusitupa, Matti I J and van Dam, Rob M and Veenstra, Jenna and Monique Verschuren, W M and Wareham, Nick and Willett, Walter and Woodward, Mark and Yuan, Jian-Min and Micha, Renata and Lemaitre, Rozenn N and Mozaffarian, Dariush and Riserus, Ulf} } @article {7972, title = {Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation.}, journal = {Circ Genom Precis Med}, volume = {12}, year = {2019}, month = {2019 Feb}, pages = {e002409}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.118.002409}, author = {D{\"o}rr, Marcus and Hamburg, Naomi M and M{\"u}ller, Christian and Smith, Nicholas L and Gustafsson, Stefan and Lehtim{\"a}ki, Terho and Teumer, Alexander and Zeller, Tanja and Li, Xiaohui and Lind, Lars and Raitakari, Olli T and V{\"o}lker, Uwe and Blankenberg, Stefan and McKnight, Barbara and Morris, Andrew P and K{\"a}h{\"o}nen, Mika and Lemaitre, Rozenn N and Wild, Philipp S and Nauck, Matthias and V{\"o}lzke, Henry and M{\"u}nzel, Thomas and Mitchell, Gary F and Psaty, Bruce M and Lindgren, Cecilia M and Larson, Martin G and Felix, Stephan B and Ingelsson, Erik and Lyytik{\"a}inen, Leo-Pekka and Herrington, David and Benjamin, Emelia J and Schnabel, Renate B} } @article {8099, title = {Genome-wide association study of breakfast skipping links clock regulation with food timing.}, journal = {Am J Clin Nutr}, year = {2019}, month = {2019 Jun 13}, abstract = {

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits.

OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait.

METHODS: We leveraged the statistical power of the UK Biobank (n~=~193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n~=~2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n~=~11,963).

RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P~=~0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P~=~0.095).

CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqz076}, author = {Dashti, Hassan S and Merino, Jordi and Lane, Jacqueline M and Song, Yanwei and Smith, Caren E and Tanaka, Toshiko and McKeown, Nicola M and Tucker, Chandler and Sun, Dianjianyi and Bartz, Traci M and Li-Gao, Ruifang and Nisa, Hoirun and Reutrakul, Sirimon and Lemaitre, Rozenn N and Alshehri, Tahani M and de Mutsert, Ren{\'e}e and Bazzano, Lydia and Qi, Lu and Knutson, Kristen L and Psaty, Bruce M and Mook-Kanamori, Dennis O and Perica, Vesna Boraska and Neuhouser, Marian L and Scheer, Frank A J L and Rutter, Martin K and Garaulet, Marta and Saxena, Richa} } @article {7970, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Jan 29}, abstract = {

An individual{\textquoteright}s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P~<~1~{\texttimes}~10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P~<~5~{\texttimes}~10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz005}, author = {de Vries, Paul S and Brown, Michael R and Bentley, Amy R and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Schwander, Karen and Kraja, Aldi T and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Deng, Xuan and Dorajoo, Rajkumar and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Evangelou, Evangelos and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Lee, Joseph H and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Riaz, Muhammad and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Ballantyne, Christie and Boerwinkle, Eric and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Connell, John M and de Faire, Ulf and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Ding, Jingzhong and Dominiczak, Anna F and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Ghanbari, Mohsen and Giulianini, Franco and Grabe, Hans J and Grove, Megan L and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Howard, Barbara V and Ikram, M Arfan and Jacobs, David R and Johnson, Craig and Jonas, Jost Bruno and Kammerer, Candace M and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Koistinen, Heikki A and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Steve B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lemaitre, Rozenn N and Li, Yize and Liang, Jingjing and Liu, Jianjun and Liu, Kiang and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Mosley, Thomas H and Mukamal, Kenneth J and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Sotoodehnia, Nona and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Reiner, Alex P and Rice, Treva K and Rich, Stephen S and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Blair H and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tan, Nicholas and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Vuckovic, Dragana and Waldenberger, Melanie and Wang, Lihua and Wang, Yujie and Wang, Zhe and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Penninx, Brenda and Pereira, Alexandre C and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Zheng, Wei and Elliott, Paul and North, Kari E and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Liu, Ching-Ti and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Kardia, Sharon L R and Zhu, Xiaofeng and Rotimi, Charles N and Mook-Kanamori, Dennis O and Fornage, Myriam and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Liu, Jingmin and Rotter, Jerome I and Gauderman, W James and Province, Michael A and Munroe, Patricia B and Rice, Kenneth and Chasman, Daniel I and Cupples, L Adrienne and Rao, Dabeeru C and Morrison, Alanna C} } @article {7976, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 22}, pages = {376}, abstract = {

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Sung, Yun Ju and Schwander, Karen and Winkler, Thomas W and Jakupovi{\'c}, Hermina and Chasman, Daniel I and Manning, Alisa and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Richard, Melissa and Wang, Heming and Wang, Zhe and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Lohman, Kurt K and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Zhao, Jing Hua and Kraja, Aldi T and Kuhnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Stringham, Heather M and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Ware, Erin B and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Arnett, Donna K and Boerwinkle, Eric and Brumat, Marco and Cade, Brian and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Eaton, Charles B and Faul, Jessica D and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jonas, Jost B and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Kritchevsky, Stephen B and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Mohlke, Karen L and Mosley, Thomas H and Murray, Alison D and Nalls, Mike A and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and O{\textquoteright}Connell, Jeff and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Poveda, Alaitz and Raitakari, Olli T and Rich, Stephen S and Risch, Neil and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Sidney, Stephen S and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and Starr, John M and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Tsai, Michael Y and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Samani, Nilesh J and Shu, Xiao-Ou and van der Harst, Pim and van Vliet-Ostaptchouk, Jana V and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and Weir, David R and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Evans, Michele K and Franks, Paul W and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Liu, Yongmei and North, Kari E and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Kardia, Sharon L R and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Redline, Susan and van Duijn, Cornelia M and Rotter, Jerome I and Kooperberg, Charles B and Gauderman, W James and Psaty, Bruce M and Rice, Kenneth and Munroe, Patricia B and Fornage, Myriam and Cupples, L Adrienne and Rotimi, Charles N and Morrison, Alanna C and Rao, Dabeeru C and Loos, Ruth J F} } @article {8105, title = {Plasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk.}, journal = {Circ Heart Fail}, volume = {12}, year = {2019}, month = {2019 Jul}, pages = {e005708}, abstract = {

BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.

METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95\% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.

CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.118.005708}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Hoofnagle, Andrew and McKnight, Barbara and Fretts, Amanda M and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona} } @article {8275, title = {Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {8}, year = {2019}, month = {2019 Nov 19}, pages = {e012881}, abstract = {

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6~years, and 13~years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13~years, median follow-up (maximum 22.4~years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95\% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95\% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95\% CI=1.08-1.41; and hazard ratio=0.78, 95\% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012881}, author = {Lai, Heidi T M and de Oliveira Otto, Marcia C and Lee, Yujin and Wu, Jason H Y and Song, Xiaoling and King, Irena B and Psaty, Bruce M and Lemaitre, Rozenn N and McKnight, Barbara and Siscovick, David S and Mozaffarian, Dariush} } @article {8410, title = {Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.}, journal = {Eur J Epidemiol}, volume = {35}, year = {2020}, month = {2020 Jul}, pages = {685-697}, abstract = {

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95\% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95\% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95\% CI - 2.45 to 1.08~mmHg), 0.06~mmHg lower diastolic blood pressure (β = - 0.06, 95\% CI - 0.93 to 0.87~mmHg), or pulse pressure (β = - 0.65, 95\% CI - 1.38 to 0.69~mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

}, issn = {1573-7284}, doi = {10.1007/s10654-020-00638-z}, author = {Zheng, Yan and Huang, Tao and Wang, Tiange and Mei, Zhendong and Sun, Zhonghan and Zhang, Tao and Ellervik, Christina and Chai, Jin-Fang and Sim, Xueling and van Dam, Rob M and Tai, E-Shyong and Koh, Woon-Puay and Dorajoo, Rajkumar and Saw, Seang-Mei and Sabanayagam, Charumathi and Wong, Tien Yin and Gupta, Preeti and Rossing, Peter and Ahluwalia, Tarunveer S and Vinding, Rebecca K and Bisgaard, Hans and B{\o}nnelykke, Klaus and Wang, Yujie and Graff, Mariaelisa and Voortman, Trudy and van Rooij, Frank J A and Hofman, Albert and van Heemst, Diana and Noordam, Raymond and Estampador, Angela C and Varga, Tibor V and Enzenbach, Cornelia and Scholz, Markus and Thiery, Joachim and Burkhardt, Ralph and Orho-Melander, Marju and Schulz, Christina-Alexandra and Ericson, Ulrika and Sonestedt, Emily and Kubo, Michiaki and Akiyama, Masato and Zhou, Ang and Kilpel{\"a}inen, Tuomas O and Hansen, Torben and Kleber, Marcus E and Delgado, Graciela and McCarthy, Mark and Lemaitre, Rozenn N and Felix, Janine F and Jaddoe, Vincent W V and Wu, Ying and Mohlke, Karen L and Lehtim{\"a}ki, Terho and Wang, Carol A and Pennell, Craig E and Schunkert, Heribert and Kessler, Thorsten and Zeng, Lingyao and Willenborg, Christina and Peters, Annette and Lieb, Wolfgang and Grote, Veit and Rzehak, Peter and Koletzko, Berthold and Erdmann, Jeanette and Munz, Matthias and Wu, Tangchun and He, Meian and Yu, Caizheng and Lecoeur, C{\'e}cile and Froguel, Philippe and Corella, Dolores and Moreno, Luis A and Lai, Chao-Qiang and Pitk{\"a}nen, Niina and Boreham, Colin A and Ridker, Paul M and Rosendaal, Frits R and de Mutsert, Ren{\'e}e and Power, Chris and Paternoster, Lavinia and S{\o}rensen, Thorkild I A and Tj{\o}nneland, Anne and Overvad, Kim and Djouss{\'e}, Luc and Rivadeneira, Fernando and Lee, Nanette R and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Langhendries, Jean-Paul and Escribano, Joaquin and Verduci, Elvira and Dedoussis, George and K{\"o}nig, Inke and Balkau, Beverley and Coltell, Oscar and Dallongeville, Jean and Meirhaeghe, Aline and Amouyel, Philippe and Gottrand, Fr{\'e}d{\'e}ric and Pahkala, Katja and Niinikoski, Harri and Hypp{\"o}nen, Elina and M{\"a}rz, Winfried and Mackey, David A and Gruszfeld, Dariusz and Tucker, Katherine L and Fumeron, Fr{\'e}d{\'e}ric and Estruch, Ramon and Ordovas, Jose M and Arnett, Donna K and Mook-Kanamori, Dennis O and Mozaffarian, Dariush and Psaty, Bruce M and North, Kari E and Chasman, Daniel I and Qi, Lu} } @article {8284, title = {Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e012853}, abstract = {

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76~years; 40\% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7~years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95\% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95\% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95\% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95\% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012853}, author = {Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and Sitlani, Colleen M and McKnight, Barbara and King, Irena B and Siscovick, David S and Psaty, Bruce M and Heckbert, Susan R and Mozaffarian, Dariush and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, <=5\%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65{\texttimes}10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} } @article {8241, title = {Serial Biomarkers of De Novo Lipogenesis Fatty Acids and Incident Heart Failure in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e014119}, abstract = {

Background De novo lipogenesis (DNL) is an endogenous pathway that converts excess dietary starch, sugar, protein, and alcohol into specific fatty acids (FAs). Although elevated DNL is linked to several metabolic abnormalities, little is known about how long-term habitual levels and changes in levels of FAs in the DNL pathway relate to incident heart failure (HF). Methods and Results We investigated whether habitual levels and changes in serial measures of FAs in the DNL pathway were associated with incident HF among 4249 participants free of HF at baseline. Plasma phospholipid FAs were measured at baseline, 6~years, and 13~years using gas chromatography, and risk factors for HF were measured using standardized methods. Incident HF was centrally adjudicated using medical records. We prospectively evaluated associations with HF risk of (1) habitual FA levels, using cumulative updating to assess long-term exposure, and (2) changes in FA levels over time. During 22.1~years of follow-up, 1304 HF cases occurred. After multivariable adjustment, habitual levels and changes in levels of palmitic acid (16:0) were positively associated with incident HF (interquintile hazard ratio [95\% CI]=1.17 [1.00-1.36] and 1.26 [1.03-1.55], respectively). Changes in levels of 7-hexadecenoic acid (16:1n-9) and vaccenic acid (18:1n-7) were each positively associated with risk of HF (1.36 [1.13-1.62], and 1.43 [1.18-1.72], respectively). Habitual levels and changes in levels of myristic acid (14:0), palmitoleic acid (16:1n-7), stearic acid (18:0), and oleic acid (18:1n-9) were not associated with incident HF. Conclusions Both habitual levels and changes in levels of 16:0 were positively associated with incident HF in older adults. Changes in 16:1n-9 and 18:1n-7 were also positively associated with incident HF. These findings support a potential role of DNL or these DNL-related FAs in the development of HF.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.014119}, author = {Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and McKnight, Barbara and King, Irena B and Song, Xiaoling and Huggins, Gordon S and Vest, Amanda R and Siscovick, David S and Mozaffarian, Dariush} } @article {8826, title = {Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 Aug 02}, pages = {e2120616}, abstract = {

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown.

Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline.

Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020.

Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid.

Results: Among the 2680 study participants (976 men [36.4\%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15\% lower risk of an unhealthy event (HR, 0.85; 95\% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16\% lower risk of an unhealthy event (HR, 0.84; 95\% CI, 0.73-0.95; P for trend = .001).

Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.20616}, author = {Bockus, Lee B and Biggs, Mary L and Lai, Heidi T M and de Olivera Otto, Marcia C and Fretts, Amanda M and McKnight, Barbara and Sotoodehnia, Nona and King, Irena B and Song, Xiaoling and Siscovick, David S and Mozaffarian, Dariush and Lemaitre, Rozenn N} } @article {8922, title = {Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 Aug 02}, pages = {e2122844}, abstract = {

Importance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.

Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).

Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.

Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.

Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.

Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61\%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95\% CI, 1.04-1.10] for TMAO; 1.07 [95\% CI, 1.03-1.10] for carnitine; 1.05 [95\% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95\% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95\% CI, 4.32-8.60] and 2.27 [95\% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95\% CI, 0.94-1.55] for TMAO; 0.96 [95\% CI, 0.74-1.24] for choline; 0.88 [95\% CI, 0.67-1.15] for betaine; 1.07 [95\% CI, 0.83-1.37] for carnitine; 0.79 [95\% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95\% CI, 0.83-1.35] for crotonobetaine).

Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.22844}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and McKnight, Barbara and Nemet, Ina and Biggs, Mary L and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {8777, title = {Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 22}, pages = {2329}, abstract = {

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18\%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Fatty Acids, Omega-3, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mortality, Premature, Prospective Studies, Protective Factors, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-021-22370-2}, author = {Harris, William S and Tintle, Nathan L and Imamura, Fumiaki and Qian, Frank and Korat, Andres V Ardisson and Marklund, Matti and Djouss{\'e}, Luc and Bassett, Julie K and Carmichael, Pierre-Hugues and Chen, Yun-Yu and Hirakawa, Yoichiro and K{\"u}pers, Leanne K and Laguzzi, Federica and Lankinen, Maria and Murphy, Rachel A and Samieri, Cecilia and Senn, Mackenzie K and Shi, Peilin and Virtanen, Jyrki K and Brouwer, Ingeborg A and Chien, Kuo-Liong and Eiriksdottir, Gudny and Forouhi, Nita G and Geleijnse, Johanna M and Giles, Graham G and Gudnason, Vilmundur and Helmer, Catherine and Hodge, Allison and Jackson, Rebecca and Khaw, Kay-Tee and Laakso, Markku and Lai, Heidi and Laurin, Danielle and Leander, Karin and Lindsay, Joan and Micha, Renata and Mursu, Jaako and Ninomiya, Toshiharu and Post, Wendy and Psaty, Bruce M and Riserus, Ulf and Robinson, Jennifer G and Shadyab, Aladdin H and Snetselaar, Linda and Sala-Vila, Aleix and Sun, Yangbo and Steffen, Lyn M and Tsai, Michael Y and Wareham, Nicholas J and Wood, Alexis C and Wu, Jason H Y and Hu, Frank and Sun, Qi and Siscovick, David S and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {8711, title = {Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 12}, pages = {2182}, abstract = {

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 {\texttimes} 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 {\texttimes} 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 {\texttimes} 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-22339-1}, author = {Natarajan, Pradeep and Pampana, Akhil and Graham, Sarah E and Ruotsalainen, Sanni E and Perry, James A and de Vries, Paul S and Broome, Jai G and Pirruccello, James P and Honigberg, Michael C and Aragam, Krishna and Wolford, Brooke and Brody, Jennifer A and Antonacci-Fulton, Lucinda and Arden, Moscati and Aslibekyan, Stella and Assimes, Themistocles L and Ballantyne, Christie M and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Do, Ron and Doddapaneni, Harsha and Emery, Leslie S and Hung, Yi-Jen and Irvin, Marguerite R and Khan, Alyna T and Lange, Leslie and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Metcalf, Ginger and Montasser, May E and Moon, Jee-Young and Muzny, Donna and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peralta, Juan M and Peyser, Patricia A and Stilp, Adrienne M and Tsai, Michael and Wang, Fei Fei and Weeks, Daniel E and Yanek, Lisa R and Wilson, James G and Abecasis, Goncalo and Arnett, Donna K and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chang, Yi-Cheng and Chen, Yii-der I and Choi, Won Jung and Correa, Adolfo and Curran, Joanne E and Daly, Mark J and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and He, Jiang and Hveem, Kristian and Jarvik, Gail P and Kaplan, Robert C and Kardia, Sharon L R and Kenny, Eimear and Kim, Ryan W and Kooperberg, Charles and Laurie, Cathy C and Lee, Seonwook and Lloyd-Jones, Don M and Loos, Ruth J F and Lubitz, Steven A and Mathias, Rasika A and Martinez, Karine A Viaud and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah A and North, Kari E and Palotie, Aarno and Park, Cheol Joo and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Seo, Daekwan and Seo, Jeong-Sun and Smith, Albert V and Tracy, Russell P and Vasan, Ramachandran S and Kathiresan, Sekar and Cupples, L Adrienne and Rotter, Jerome I and Morrison, Alanna C and Rich, Stephen S and Ripatti, Samuli and Willer, Cristen and Peloso, Gina M} } @article {8910, title = {Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.}, journal = {Clin Chem}, volume = {67}, year = {2021}, month = {2021 Nov 26}, pages = {1650-1659}, abstract = {

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.

METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged >=65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.

RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95\% CI), 1.65-2.17 for Cer-16, 0.79 (95\% CI, 0.70-0.88) for Cer-22, 0.74 (95\% CI, 0.65-0.84) for Cer-24, 2.51 (95\% CI, 2.01-3.14) for SM-16, 0.68 (95\% CI, 0.58-0.79) for SM-20, 0.57 (95\% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.

CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

}, issn = {1530-8561}, doi = {10.1093/clinchem/hvab182}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8831, title = {Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults.}, journal = {J Am Heart Assoc}, year = {2021}, month = {2021 Aug 16}, pages = {e020646}, abstract = {

Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7~years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6\%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95\% CI, 1.02-1.42; -trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95\% CI, 0.90-1.27), as well as modified by eGFR (-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60~mL/min per 1.73~m: HR, 1.56 [95\% CI, 1.13-2.14]; -trend=0.007), but not normal or mildly reduced renal function (eGFR >=60~mL/min per 1.73~m: HR, 1.03 [95\% CI, 0.85-1.25]; -trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95\% CI, 1.01-1.56]; -trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

}, issn = {2047-9980}, doi = {10.1161/JAHA.120.020646}, author = {Lee, Yujin and Nemet, Ina and Wang, Zeneng and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Fretts, Amanda M and Sotoodehnia, Nona and Budoff, Matthew and DiDonato, Joseph A and McKnight, Barbara and Tang, W H Wilson and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {8909, title = {Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes.}, journal = {J Lipid Res}, year = {2021}, month = {2021 Sep 20}, pages = {100119}, abstract = {

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20\%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose >=126 mg/dL or non-fasting glucose >=200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95\% CI 1.09-1.34) for Cer-16, 1.23 (95\% CI 1.10-1.37) for Cer-18, 1.14 (95\% CI 1.02-1.26) for Cer-20, and 1.18 (95\% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

}, issn = {1539-7262}, doi = {10.1016/j.jlr.2021.100119}, author = {Fretts, Amanda M and Jensen, Paul N and Hoofnagle, Andrew N and McKnight, Barbara and Howard, Barbara V and Umans, Jason and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Djouss{\'e}, Luc and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {8704, title = {Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.}, journal = {Cardiology}, year = {2021}, month = {2021 Feb 25}, pages = {1-8}, abstract = {

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 {\textpm} 4.4 years, and 38.8\% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95\% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

}, issn = {1421-9751}, doi = {10.1159/000513917}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Matthan, Nirupa R and Ix, Joachim H and Fitzpatrick, Annette L and King, Irena and Lemaitre, Rozenn N and McKnight, Barbara and Kizer, Jorge R and Lichtenstein, Alice H and Mukamal, Kenneth J and Siscovick, David S} } @article {8830, title = {Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Aug}, pages = {e003288}, abstract = {

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95\% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95\% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003288}, author = {Haslam, Danielle E and Peloso, Gina M and Guirette, Melanie and Imamura, Fumiaki and Bartz, Traci M and Pitsillides, Achilleas N and Wang, Carol A and Li-Gao, Ruifang and Westra, Jason M and Pitk{\"a}nen, Niina and Young, Kristin L and Graff, Mariaelisa and Wood, Alexis C and Braun, Kim V E and Luan, Jian{\textquoteright}an and K{\"a}h{\"o}nen, Mika and Kiefte-de Jong, Jessica C and Ghanbari, Mohsen and Tintle, Nathan and Lemaitre, Rozenn N and Mook-Kanamori, Dennis O and North, Kari and Helminen, Mika and Mossavar-Rahmani, Yasmin and Snetselaar, Linda and Martin, Lisa W and Viikari, Jorma S and Oddy, Wendy H and Pennell, Craig E and Rosendall, Frits R and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Mozaffarian, Dariush and Rotter, Jerome I and Taylor, Kent D and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Livingston, Kara A and Voortman, Trudy and Forouhi, Nita G and Wareham, Nick J and de Mutsert, Ren{\'e}e and Rich, Steven S and Manson, JoAnn E and Mora, Samia and Ridker, Paul M and Merino, Jordi and Meigs, James B and Dashti, Hassan S and Chasman, Daniel I and Lichtenstein, Alice H and Smith, Caren E and Dupuis, Jos{\'e}e and Herman, Mark A and McKeown, Nicola M} } @article {9091, title = {Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2213242}, abstract = {

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.

Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.

Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.

Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.

Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.

Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3\%) were male, 3184 (59.7\%) were female, 848 (15.9\%) were African American, 4450 (83.4\%) were White, and 35 (0.01\%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95\% CI, 1.17-1.44) for TMAO, 1.19 (95\% CI, 1.08-1.32) for choline, 1.26 (95\% CI, 1.15-1.40) for carnitine, and 1.26 (95\% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.

Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

}, keywords = {Aged, Betaine, Cardiovascular Diseases, Carnitine, Choline, Cohort Studies, Female, Humans, Male, Methylamines, Prospective Studies}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.13242}, author = {Fretts, Amanda M and Hazen, Stanley L and Jensen, Paul and Budoff, Matthew and Sitlani, Colleen M and Wang, Meng and de Oliveira Otto, Marcia C and DiDonato, Joseph A and Lee, Yujin and Psaty, Bruce M and Siscovick, David S and Sotoodehnia, Nona and Tang, W H Wilson and Lai, Heidi and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {9182, title = {Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {42}, year = {2022}, month = {2022 09}, pages = {e273-e288}, abstract = {

BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways.

METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways.

RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95\% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95\% CI) of 10.6\% (1.0-114.5), 7.8\% (1.0-32.7), and 9.2\% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association.

CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.

}, keywords = {Animals, Atherosclerosis, Cardiovascular Diseases, Carnitine, Humans, Meat, Methylamines, Risk Factors}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.121.316533}, author = {Wang, Meng and Wang, Zeneng and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Fretts, Amanda and Sotoodehnia, Nona and Budoff, Matthew and DiDonato, Joseph A and McKnight, Barbara and Tang, W H Wilson and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9157, title = {Longitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study.}, journal = {J Alzheimers Dis}, year = {2022}, month = {2022 Sep 02}, abstract = {

BACKGROUND: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear.

OBJECTIVE: We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS).

METHODS: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models.

RESULTS: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20-32\% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with \~{}25\% lower risk of the same cognitive outcomes per IQR.||Conclusion:These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.

}, issn = {1875-8908}, doi = {10.3233/JAD-220477}, author = {de Oliveira Otto, Marcia C and Li, Xinmin S and Wang, Zeneng and Siscovick, David and Newman, Anne B and Lai, Heidi Tsz Mung and Nemet, Ina and Lee, Yujin and Wang, Meng and Fretts, Amanda and Lemaitre, Rozenn N and Tang, W H Wilson and Lopez, Oscar and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9171, title = {Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.}, journal = {EBioMedicine}, volume = {83}, year = {2022}, month = {2022 Sep}, pages = {104189}, abstract = {

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free~+~esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95\% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95\% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

}, keywords = {Animals, Arachidonic Acids, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Eicosanoids, Humans, Ischemic Stroke, Prospective Studies}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2022.104189}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Zeigler, Maxwell and Fretts, Amanda M and Umans, Jason G and Howard, Barbara V and Sitlani, Colleen M and McKnight, Barbara and Gharib, Sina A and King, Irena B and Siscovick, David S and Psaty, Bruce M and Sotoodehnia, Nona and Totah, Rheem A} } @article {9086, title = {Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.}, journal = {Eur J Epidemiol}, year = {2022}, month = {2022 Jul 05}, abstract = {

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61\% women, mean age 74~years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

}, issn = {1573-7284}, doi = {10.1007/s10654-022-00888-z}, author = {Austin, Thomas R and McHugh, Caitlin P and Brody, Jennifer A and Bis, Joshua C and Sitlani, Colleen M and Bartz, Traci M and Biggs, Mary L and Bansal, Nisha and B{\r u}zkov{\'a}, Petra and Carr, Steven A and deFilippi, Christopher R and Elkind, Mitchell S V and Fink, Howard A and Floyd, James S and Fohner, Alison E and Gerszten, Robert E and Heckbert, Susan R and Katz, Daniel H and Kizer, Jorge R and Lemaitre, Rozenn N and Longstreth, W T and McKnight, Barbara and Mei, Hao and Mukamal, Kenneth J and Newman, Anne B and Ngo, Debby and Odden, Michelle C and Vasan, Ramachandran S and Shojaie, Ali and Simon, Noah and Smith, George Davey and Davies, Neil M and Siscovick, David S and Sotoodehnia, Nona and Tracy, Russell P and Wiggins, Kerri L and Zheng, Jie and Psaty, Bruce M} } @article {9455, title = {PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE).}, journal = {Am J Clin Nutr}, volume = {115}, year = {2022}, month = {2022 Mar 04}, pages = {864-876}, abstract = {

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA~+~DPA~+~DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n~=~18,791) was categorized as short (<=6 h), 7-8 h (reference), or long (>=9 h). Difficulty falling asleep (8 cohorts, n~=~12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95\% CIs) for long sleep were 0.78 (95\% CI: 0.65, 0.95) for DHA and 0.76 (95\% CI: 0.63, 0.93) for EPA~+~DPA~+~DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

}, keywords = {Biomarkers, Cohort Studies, Cross-Sectional Studies, Fatty Acids, Fatty Acids, Omega-3, Humans, Outcome Assessment, Health Care, Sleep}, issn = {1938-3207}, doi = {10.1093/ajcn/nqab408}, author = {Murphy, Rachel A and Tintle, Nathan and Harris, William S and Darvishian, Maryam and Marklund, Matti and Virtanen, Jyrki K and Hantunen, Sari and de Mello, Vanessa D and Tuomilehto, Jaakko and Lindstr{\"o}m, Jaana and Bolt, Matthew A and Brouwer, Ingeborg A and Wood, Alexis C and Senn, Mackenzie and Redline, Susan and Tsai, Michael Y and Gudnason, Vilmundur and Eiriksdottir, Gudny and Lindberg, Eva and Shadyab, Aladdin H and Liu, Buyun and Carnethon, Mercedes and Uusitupa, Matti and Djouss{\'e}, Luc and Riserus, Ulf and Lind, Lars and van Dam, Rob M and Koh, Woon-Puay and Shi, Peilin and Siscovick, David and Lemaitre, Rozenn N and Mozaffarian, Dariush} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1\%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9456, title = {Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.}, journal = {BMJ}, volume = {380}, year = {2023}, month = {2023 Jan 18}, pages = {e072909}, abstract = {

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75\% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3\%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95\% confidence interval 0.86 to 0.98; P=0.009, I=9.9\%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13\% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0\%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8\%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (>=60 <60 years), estimated glomerular filtration rate (60-89 >=90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

}, keywords = {alpha-Linolenic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Humans, Middle Aged, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors}, issn = {1756-1833}, doi = {10.1136/bmj-2022-072909}, author = {Ong, Kwok Leung and Marklund, Matti and Huang, Liping and Rye, Kerry-Anne and Hui, Nicholas and Pan, Xiong-Fei and Rebholz, Casey M and Kim, Hyunju and Steffen, Lyn M and van Westing, Anniek C and Geleijnse, Johanna M and Hoogeveen, Ellen K and Chen, Yun-Yu and Chien, Kuo-Liong and Fretts, Amanda M and Lemaitre, Rozenn N and Imamura, Fumiaki and Forouhi, Nita G and Wareham, Nicholas J and Birukov, Anna and J{\"a}ger, Susanne and Kuxhaus, Olga and Schulze, Matthias B and de Mello, Vanessa Derenji and Tuomilehto, Jaakko and Uusitupa, Matti and Lindstr{\"o}m, Jaana and Tintle, Nathan and Harris, William S and Yamasaki, Keisuke and Hirakawa, Yoichiro and Ninomiya, Toshiharu and Tanaka, Toshiko and Ferrucci, Luigi and Bandinelli, Stefania and Virtanen, Jyrki K and Voutilainen, Ari and Jayasena, Tharusha and Thalamuthu, Anbupalam and Poljak, Anne and Bustamante, Sonia and Sachdev, Perminder S and Senn, Mackenzie K and Rich, Stephen S and Tsai, Michael Y and Wood, Alexis C and Laakso, Markku and Lankinen, Maria and Yang, Xiaowei and Sun, Liang and Li, Huaixing and Lin, Xu and Nowak, Christoph and Arnl{\"o}v, Johan and Riserus, Ulf and Lind, Lars and Le Goff, M{\'e}lanie and Samieri, Cecilia and Helmer, Catherine and Qian, Frank and Micha, Renata and Tin, Adrienne and K{\"o}ttgen, Anna and de Boer, Ian H and Siscovick, David S and Mozaffarian, Dariush and Wu, Jason HY} } @article {9477, title = {Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.}, journal = {J Alzheimers Dis}, year = {2023}, month = {2023 Aug 23}, abstract = {

BACKGROUND: Comprising nearly 35\% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged>=65 years in the Cardiovascular Health Study.

METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95\% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95\% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

}, issn = {1875-8908}, doi = {10.3233/JAD-230083}, author = {de Oliveira Otto, Marcia C and Wu, Jason H Y and Thacker, Evan L and Lai, Heidi Tsz Mung and Lemaitre, Rozenn N and Padhye, Nikhil and Song, Xiaoling and King, Irena B and Lopez, Oscar and Siscovick, David S and Mozaffarian, Dariush} } @article {9482, title = {Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events.}, journal = {EBioMedicine}, volume = {95}, year = {2023}, month = {2023 Aug 24}, pages = {104765}, abstract = {

BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

FINDINGS: The mean ({\textpm}SD) eGFR was 70 ({\textpm}16) mL/min/1.73~m; 62\% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13\%, 95\% CI 8-22\%) and sphingomyelin-16:0 (proportion mediated 10\%, 95\% CI 5-17\%). No sphingolipids mediated the association between eGFR and ischemic stroke.

INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr.~Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr.~Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2023.104765}, author = {Lidgard, Benjamin and Bansal, Nisha and Zelnick, Leila R and Hoofnagle, Andrew N and Fretts, Amanda M and Longstreth, William T and Shlipak, Michael G and Siscovick, David S and Umans, Jason G and Lemaitre, Rozenn N} } @article {9583, title = {Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.}, journal = {medRxiv}, year = {2023}, month = {2023 Nov 11}, abstract = {

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).

METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91\% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.

RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42{\textpm}0.09 mm Hg (P for interaction = 9.4e-7) and 0.20{\textpm}0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.

CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

}, doi = {10.1101/2023.11.10.23298402}, author = {Guirette, Melanie and Lan, Jessie and McKeown, Nicola and Brown, Michael R and Chen, Han and de Vries, Paul S and Kim, Hyunju and Rebholz, Casey M and Morrison, Alanna C and Bartz, Traci M and Fretts, Amanda M and Guo, Xiuqing and Lemaitre, Rozenn N and Liu, Ching-Ti and Noordam, Raymond and de Mutsert, Ren{\'e}e and Rosendaal, Frits R and Wang, Carol A and Beilin, Lawrence and Mori, Trevor A and Oddy, Wendy H and Pennell, Craig E and Chai, Jin Fang and Whitton, Clare and van Dam, Rob M and Liu, Jianjun and Tai, E Shyong and Sim, Xueling and Neuhouser, Marian L and Kooperberg, Charles and Tinker, Lesley and Franceschini, Nora and Huan, Tianxiao and Winkler, Thomas W and Bentley, Amy R and Gauderman, W James and Heerkens, Luc and Tanaka, Toshiko and van Rooij, Jeroen and Munroe, Patricia B and Warren, Helen R and Voortman, Trudy and Chen, Honglei and Rao, D C and Levy, Daniel and Ma, Jiantao} } @article {9533, title = {Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Nov 01}, pages = {e2343854}, abstract = {

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1\%] women; 6 [0.1\%] American Indian; 4 [0.1\%] Asian; 718 [15.6\%] Black; 3869 [83.9\%] White, and 15 [0.3\%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95\% CI, 1.12-1.59]; HR for SM-16, 1.37 [95\% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95\% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95\% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95\% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95\% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95\% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95\% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

}, keywords = {Aged, Ceramides, Cohort Studies, Death, Sudden, Cardiac, Eicosanoic Acids, Fatty Acids, Female, Humans, Male, Sphingolipids, Sphingomyelins}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.43854}, author = {Bockus, Lee B and Jensen, Paul N and Fretts, Amanda M and Hoofnagle, Andrew N and McKnight, Barbara and Sitlani, Colleen M and Siscovick, David S and King, Irena B and Psaty, Bruce M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9330, title = {Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.}, journal = {ERJ Open Res}, volume = {9}, year = {2023}, month = {2023 Mar}, abstract = {

RATIONALE: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function.

METHODS: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV) and odds of COPD, respectively.

RESULTS: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD.

CONCLUSION: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV within individuals or with incident COPD.

}, issn = {2312-0541}, doi = {10.1183/23120541.00346-2022}, author = {Gharib, Arya R and Jensen, Paul N and Psaty, Bruce M and Hoofnagle, Andrew N and Siscovick, David and Gharib, Sina A and Sitlani, Colleen M and Sotoodehnia, Nona and Lemaitre, Rozenn N} } @article {9451, title = {Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Aug 15}, pages = {e8711}, abstract = {

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60\% (CHS) and 53\% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Atherosclerosis, Female, Humans, Ischemic Stroke, Methylamines, Oxides, Prospective Studies, Risk Factors, Stroke, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029230}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and Sitlani, Colleen M and Nemet, Ina and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Zhu, Weifei and Budoff, Matt and Longstreth, W T and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9376, title = {Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 May 30}, pages = {3111}, abstract = {

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

}, keywords = {Ethnicity, Genome-Wide Association Study, Humans, Metabolome, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {2041-1723}, doi = {10.1038/s41467-023-38800-2}, author = {Feofanova, Elena V and Brown, Michael R and Alkis, Taryn and Manuel, Astrid M and Li, Xihao and Tahir, Usman A and Li, Zilin and Mendez, Kevin M and Kelly, Rachel S and Qi, Qibin and Chen, Han and Larson, Martin G and Lemaitre, Rozenn N and Morrison, Alanna C and Grieser, Charles and Wong, Kari E and Gersztern, Robert E and Zhao, Zhongming and Lasky-Su, Jessica and Yu, Bing} } @article {9704, title = {Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.}, journal = {Front Neurol}, volume = {15}, year = {2024}, month = {2024}, pages = {1385623}, abstract = {

BACKGROUND: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

METHODS: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40\% male; and 25\% ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

RESULTS: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected () = 0.004 and β = 0.06, = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95\%CI: 1.07, 1.49), = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

CONCLUSION: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

}, issn = {1664-2295}, doi = {10.3389/fneur.2024.1385623}, author = {Moseholm, Kristine F and Horn, Jens W and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Longstreth, W T and Lopez, Oscar L and Hoofnagle, Andrew N and Jensen, Majken K and Lemaitre, Rozenn N and Mukamal, Kenneth J} } @article {9743, title = {Circulating sphingolipids in relation to cognitive decline and incident dementia: The Cardiovascular Health Study.}, journal = {Alzheimers Dement (Amst)}, volume = {16}, year = {2024}, month = {2024 Jul-Sep}, pages = {e12623}, abstract = {

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain.

METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40\% male; and 25\% apolipoprotein E ( ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia.

RESULTS: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR]~=~1.24 [95\% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR~=~1.26 [95\% CI: 1.10-1.45]) were associated with higher risk of incident dementia.

DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk.

HIGHLIGHTS: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

}, issn = {2352-8729}, doi = {10.1002/dad2.12623}, author = {Moseholm, Kristine F and Cronj{\'e}, H{\'e}l{\'e}ne T and Koch, Manja and Fitzpatrick, Annette L and Lopez, Oscar L and Otto, Marcia C de Oliveira and Longstreth, W T and Hoofnagle, Andrew N and Mukamal, Kenneth J and Lemaitre, Rozenn N and Jensen, Majken K} } @article {9648, title = {The Gut Microbial Metabolite Trimethylamine N-oxide, Incident CKD, and Kidney Function Decline.}, journal = {J Am Soc Nephrol}, year = {2024}, month = {2024 Apr 09}, abstract = {

BACKGROUND: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline.

METHODS: We included 10,564 participants from two community-based, prospective cohorts with estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and Cystatin C were measured up to 4 times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline >= 30\% from baseline and a resulting eGFR<60 ml/min/1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels.

RESULTS: During a median follow-up of 9.4 years (interquartile range: 9.1-11.6 years), 979 incident CKD events occurred. Higher TMAO levels associated with higher risk of incident CKD (2nd to 5th vs. 1st quintile HR[95\%CI]= 1.65 [1.22-2.23], 1.68 [1.26-2.25], 2.28 [1.72-3.02], and 2.24[1.68-2.98], respectively) and greater annualized eGFR decline ( 2nd to 5th vs. 1st quintile annualized eGFR change= -0.21 [-0.32, -0.09], -0.17 [-0.29, -0.05], -0.35 [-0.47, -0.22], and -0.43[-0.56, -0.30], respectively) with monotonic dose-response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors including diabetes, per 10 mmHg of higher systolic blood pressure, per 10 years of older age, and Black race.

CONCLUSIONS: In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.

}, issn = {1533-3450}, doi = {10.1681/ASN.0000000000000344}, author = {Wang, Meng and Tang, W H Wilson and Li, Xinmin S and de Oliveira Otto, Marcia C and Lee, Yujin and Lemaitre, Rozenn N and Fretts, Amanda and Nemet, Ina and Sotoodehnia, Nona and Sitlani, Colleen M and Budoff, Matthew and DiDonato, Joseph A and Wang, Zeneng and Bansal, Nisha and Shlipak, Michael G and Psaty, Bruce M and Siscovick, David S and Sarnak, Mark J and Mozaffarian, Dariush and Hazen, Stanley L} } @article {9587, title = {Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.}, journal = {Circulation}, volume = {149}, year = {2024}, month = {2024 Jan 23}, pages = {305-316}, abstract = {

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels <=25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having >=1 first-degree relative who experienced a CVD event. Relative risks with 95\% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95\% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95\% CI, 1.30-1.54), whereas it was 1.25 (95\% CI, 1.16-1.33) for family history alone and 1.06 (95\% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

}, keywords = {Animals, Biomarkers, Cardiovascular Diseases, Docosahexaenoic Acids, Fatty Acids, Omega-3, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.123.065530}, author = {Laguzzi, Federica and {\r A}kesson, Agneta and Marklund, Matti and Qian, Frank and Gigante, Bruna and Bartz, Traci M and Bassett, Julie K and Birukov, Anna and Campos, Hannia and Hirakawa, Yoichiro and Imamura, Fumiaki and J{\"a}ger, Susanne and Lankinen, Maria and Murphy, Rachel A and Senn, Mackenzie and Tanaka, Toshiko and Tintle, Nathan and Virtanen, Jyrki K and Yamagishi, Kazumasa and Allison, Matthew and Brouwer, Ingeborg A and de Faire, Ulf and Eiriksdottir, Gudny and Ferrucci, Luigi and Forouhi, Nita G and Geleijnse, Johanna M and Hodge, Allison M and Kimura, Hitomi and Laakso, Markku and Riserus, Ulf and van Westing, Anniek C and Bandinelli, Stefania and Baylin, Ana and Giles, Graham G and Gudnason, Vilmundur and Iso, Hiroyasu and Lemaitre, Rozenn N and Ninomiya, Toshiharu and Post, Wendy S and Psaty, Bruce M and Salonen, Jukka T and Schulze, Matthias B and Tsai, Michael Y and Uusitupa, Matti and Wareham, Nicholas J and Oh, Seung-Won and Wood, Alexis C and Harris, William S and Siscovick, David and Mozaffarian, Dariush and Leander, Karin} } @article {9747, title = {Trimethylamine -Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.}, journal = {Circ Heart Fail}, volume = {17}, year = {2024}, month = {2024 Aug}, pages = {e011569}, abstract = {

BACKGROUND: Growing evidence indicates that trimethylamine -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF).

METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors.

RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine -oxide (hazard ratio, 1.15 [95\% CI, 1.09-1.20]; <0.001), choline (hazard ratio, 1.44 [95\% CI, 1.26-1.64]; <0.001), and crotonobetaine (hazard ratio, 1.24 [95\% CI, 1.16-1.32]; <0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race.

CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF.

REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

}, keywords = {Aged, Aged, 80 and over, Betaine, Biomarkers, Carnitine, Choline, Female, Gastrointestinal Microbiome, Heart Failure, Humans, Incidence, Male, Methylamines, Middle Aged, Risk Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.124.011569}, author = {Tang, W H Wilson and Lemaitre, Rozenn N and Jensen, Paul N and Wang, Meng and Wang, Zeneng and Li, Xinmin S and Nemet, Ina and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Fretts, Amanda M and Sotoodehnia, Nona and DiDonato, Joseph A and B{\"a}ckhed, Fredrik and Psaty, Bruce M and Siscovick, David S and Budoff, Matthew J and Mozaffarian, Dariush and Hazen, Stanley L} }