@article {696, title = {Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {22}, year = {2002}, month = {2002 Jul 01}, pages = {1175-80}, abstract = {

OBJECTIVES: Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.

METHODS AND RESULTS: The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 "healthy" participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg\% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between "healthy" participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.

CONCLUSIONS: Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.

}, keywords = {Aged, Aging, Cardiovascular System, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Health Status, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Magnetic Resonance Spectroscopy, Male, Nuclear Magnetic Resonance, Biomolecular, Risk Factors, Sex Factors}, issn = {1524-4636}, doi = {10.1161/01.atv.0000022015.97341.3a}, author = {Kuller, Lewis and Arnold, Alice and Tracy, Russell and Otvos, James and Burke, Greg and Psaty, Bruce and Siscovick, David and Freedman, David S and Kronmal, Richard} } @article {770, title = {The Cardiovascular Health Study: risk factors, subclinical disease, and clinical cardiovascular disease in older adults.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 Mar-Apr}, pages = {59-60}, keywords = {Aged, Cardiovascular Diseases, Female, Geriatric Assessment, Humans, Male, Risk Factors}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02126.x}, author = {Newman, Anne B and Siscovick, David} } @article {773, title = {Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 Mar-Apr}, pages = {81-90}, abstract = {

In the Cardiovascular Health Study, the authors sought to evaluate the impact of chronic renal insufficiency (CRI) on cardiovascular risk status and outcomes in a representative sample of community-dwelling elderly adults. Defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men, CRI was present in 647 (11\%) of 5808 participants. At baseline, the prevalence of clinical or subclinical cardiovascular disease was 64\% in participants with CRI and 43\% in those without CRI (odds ratio, 2.34; 95\% confidence interval, 1.96-2.80). The incidence of cardiovascular disease events during follow-up was 3\% per year in participants with creatinine levels <1.10 mg/dL and increased steadily to reach 7\% per year in those with creatinine > or =1.70 mg/dL. Among the possible mediators for the association between CRI and cardiovascular morbidity are inflammatory (C-reactive protein, fibrinogen, and interleukin-6) and hemostatic (factor VII, factor VIII, plasmin-antiplasmin product, and D-dimer) biomarkers, all of which were significantly elevated in Cardiovascular Health Study participants with CRI. Future studies should evaluate the contribution of novel and traditional cardiovascular risk factors to the cardiovascular risk of elderly persons with CRI. The identification of CRI in the elderly and the use of cardiovascular prevention therapies represent a major opportunity to reduce their burden of cardiovascular morbidity.

}, keywords = {Aged, Blood Coagulation Factors, Cardiovascular Diseases, Chronic Disease, Creatinine, Cystatin C, Cystatins, Female, Fibrinogen, Geriatric Assessment, Humans, Incidence, Male, Prevalence, Renal Insufficiency, Risk Factors}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02125.x}, author = {Shlipak, Michael G and Fried, Linda F and Stehman-Breen, Catherine and Siscovick, David and Newman, Anne B} } @article {775, title = {The presence of frailty in elderly persons with chronic renal insufficiency.}, journal = {Am J Kidney Dis}, volume = {43}, year = {2004}, month = {2004 May}, pages = {861-7}, abstract = {

BACKGROUND: Frailty has been defined as a tool to define individuals who lack functional reserve and are at risk for functional decline. We hypothesized that chronic renal insufficiency (CRI) would be associated with a greater prevalence of frailty and disability in the elderly.

METHODS: This cross-sectional analysis used baseline data collected from the Cardiovascular Health Study, which enrolled 5,888 community-dwelling adults aged 65 years or older from 4 clinical centers in the United States. Renal insufficiency is defined as a serum creatinine level of 1.3 mg/dL or greater (> or =115 micromol/L) in women and 1.5 mg/dL or greater (> or =133 micromol/L) in men. Frailty is defined by the presence of 3 of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. Disability is defined as any self-reported difficulty with activities of daily living.

RESULTS: Among 5,808 participants with creatinine levels measured at entry, 15.9\% of men (n = 394) and 7.6\% of women (n = 254) had CRI. Prevalences of frailty (15\% versus 6\%; P < 0.001) and disability (12\% versus 7\%; P = 0.001) were greater in participants with CRI compared with those with normal renal function. After multivariate adjustment for comorbidity, CRI remained significantly associated with frailty (odds ratio, 1.76; 95\% confidence interval, 1.28 to 2.41), but not disability (odds ratio, 1.26; 95\% confidence interval, 0.94 to 1.69).

CONCLUSION: Elderly persons with CRI have a high prevalence of frailty, which may signal their risk for progression to adverse health outcomes. If confirmed in other studies, identification of frailty in patients with CRI may warrant special interventions to preserve their independence, quality of life, and survival.

}, keywords = {Activities of Daily Living, Aged, Cross-Sectional Studies, Female, Frail Elderly, Humans, Kidney Failure, Chronic, Male, United States}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2003.12.049}, author = {Shlipak, Michael G and Stehman-Breen, Catherine and Fried, Linda F and Song, Xiao and Siscovick, David and Fried, Linda P and Psaty, Bruce M and Newman, Anne B} } @article {856, title = {Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {150}, year = {2005}, month = {2005 Sep}, pages = {464-70}, abstract = {

BACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF.

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF.

RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95\% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40\% and those with ejection fraction of > or = 40\% (HR 0.56, 95\% CI 0.27-1.13; HR 0.82, 95\% CI 0.56-1.22, respectively; interaction P = .34).

CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.

}, keywords = {Adrenergic beta-Antagonists, Age Factors, Aged, Aged, 80 and over, Female, Follow-Up Studies, Heart Failure, Humans, Male}, issn = {1097-6744}, doi = {10.1016/j.ahj.2004.12.022}, author = {Chan, Jeannie D and Rea, Thomas D and Smith, Nicholas L and Siscovick, David and Heckbert, Susan R and Lumley, Thomas and Chaves, Paulo and Furberg, Curt D and Kuller, Lewis and Psaty, Bruce M} } @article {831, title = {Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors.}, journal = {JAMA}, volume = {293}, year = {2005}, month = {2005 Apr 13}, pages = {1737-45}, abstract = {

CONTEXT: Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown.

OBJECTIVE: To compare traditional and novel risk factors as predictors of cardiovascular mortality.

DESIGN, SETTING, AND PATIENTS: A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years.

MAIN OUTCOME MEASURES: Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2.

RESULTS: Among the participants, 1249 (22\%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95\% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95\% confidence interval, 0.71-0.78; P for difference = .15).

CONCLUSIONS: Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.

}, keywords = {Aged, Cardiovascular Diseases, Chronic Disease, Humans, Kidney Diseases, Longitudinal Studies, Risk Factors}, issn = {1538-3598}, doi = {10.1001/jama.293.14.1737}, author = {Shlipak, Michael G and Fried, Linda F and Cushman, Mary and Manolio, Teri A and Peterson, Do and Stehman-Breen, Catherine and Bleyer, Anthony and Newman, Anne and Siscovick, David and Psaty, Bruce} } @article {827, title = {Cystatin C concentration as a risk factor for heart failure in older adults.}, journal = {Ann Intern Med}, volume = {142}, year = {2005}, month = {2005 Apr 05}, pages = {497-505}, abstract = {

BACKGROUND: Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function.

OBJECTIVE: To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure.

DESIGN: Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months.

SETTING: Adults 65 years of age or older from 4 communities in the United States.

PARTICIPANTS: 4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine.

MEASUREMENTS: Incident heart failure.

RESULTS: The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17\%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95\% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]).

LIMITATIONS: The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear.

CONCLUSIONS: The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.

}, keywords = {Aged, Biomarkers, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Incidence, Kidney, Kidney Function Tests, Male, Risk Factors, United States}, issn = {1539-3704}, doi = {10.7326/0003-4819-142-7-200504050-00008}, author = {Sarnak, Mark J and Katz, Ronit and Stehman-Breen, Catherine O and Fried, Linda F and Jenny, Nancy Swords and Psaty, Bruce M and Newman, Anne B and Siscovick, David and Shlipak, Michael G} } @article {876, title = {Cystatin-C and inflammatory markers in the ambulatory elderly.}, journal = {Am J Med}, volume = {118}, year = {2005}, month = {2005 Dec}, pages = {1416}, abstract = {

PURPOSE: Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.

METHODS: This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.

RESULTS: After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95\% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.

CONCLUSIONS: The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.

}, keywords = {Age Factors, Aged, Biomarkers, C-Reactive Protein, Cross-Sectional Studies, Cystatin C, Cystatins, Female, Fibrinogen, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Predictive Value of Tests, Sensitivity and Specificity}, issn = {1555-7162}, doi = {10.1016/j.amjmed.2005.07.060}, author = {Shlipak, Michael G and Katz, Ronit and Cushman, Mary and Sarnak, Mark J and Stehman-Breen, Catherine and Psaty, Bruce M and Siscovick, David and Tracy, Russell P and Newman, Anne and Fried, Linda} } @article {816, title = {Cystatin-C and mortality in elderly persons with heart failure.}, journal = {J Am Coll Cardiol}, volume = {45}, year = {2005}, month = {2005 Jan 18}, pages = {268-71}, abstract = {

OBJECTIVES: We sought to evaluate cystatin-C, a novel measure of renal function, as a predictor of mortality in elderly persons with heart failure (HF) and to compare it with creatinine.

BACKGROUND: Renal function is an important prognostic factor in patients with HF, but creatinine levels, which partly reflect muscle mass, may be insensitive for detecting renal insufficiency.

METHODS: A total of 279 Cardiovascular Health Study participants with prevalent HF and measures of serum cystatin-C and creatinine were followed for mortality outcomes over a median of 6.5 years.

RESULTS: Median creatinine and cystatin-C levels were 1.05 mg/dl and 1.26 mg/l. Each standard deviation increase in cystatin-C (0.35 mg/l) was associated with a 31\% greater adjusted mortality risk (95\% confidence interval [CI] 20\% to 43\%, p < 0.001), whereas each standard deviation increase in creatinine (0.39 mg/dl) was associated with a 17\% greater adjusted mortality risk (95\% CI 1\% to 36\%, p = 0.04). When both measures were combined in a single adjusted model, cystatin-C remained associated with elevated mortality risk (hazard ratio 1.60, 95\% CI 1.32 to 1.94), whereas creatinine levels appeared associated with lower risk (hazard ratio 0.73, 95\% CI 0.57 to 0.95).

CONCLUSIONS: Cystatin-C is a stronger predictor of mortality than creatinine in elderly persons with HF. If confirmed in future studies, this new marker of renal function could improve risk stratification in patients with HF.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Male, Pilot Projects, Predictive Value of Tests, Risk Assessment, Survival Analysis}, issn = {0735-1097}, doi = {10.1016/j.jacc.2004.09.061}, author = {Shlipak, Michael G and Katz, Ronit and Fried, Linda F and Jenny, Nancy Swords and Stehman-Breen, Catherine O and Newman, Anne B and Siscovick, David and Psaty, Bruce M and Sarnak, Mark J} } @article {865, title = {Kidney function as a predictor of noncardiovascular mortality.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3728-35}, abstract = {

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95\% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Cohort Studies, Confidence Intervals, Creatinine, Cystatin C, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Longitudinal Studies, Male, Probability, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Survival Analysis, United States}, issn = {1046-6673}, doi = {10.1681/ASN.2005040384}, author = {Fried, Linda F and Katz, Ronit and Sarnak, Mark J and Shlipak, Michael G and Chaves, Paulo H M and Jenny, Nancy Swords and Stehman-Breen, Catherine and Gillen, Dan and Bleyer, Anthony J and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {899, title = {Education, cognitive test scores, and black-white differences in dementia risk.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Jun}, pages = {898-905}, abstract = {

OBJECTIVES: To compare dementia risks of elderly black and white subjects and to determine whether differences in education and cognitive test scores contribute to the inconsistency in reported differences between these groups.

DESIGN: Longitudinal, 6-year follow-up.

PARTICIPANTS: Two thousand seven hundred eighty-six older black and white subjects in the Cardiovascular Health Study.

MEASUREMENTS: Age, education (>10 years vs < or =10 years), Modified Mini-Mental State Examination score (3MS, < or =85 vs >85). Potential confounders were sex, depression, apolipoprotein E4 genotype, vascular disease, and baseline magnetic resonance imaging changes.

RESULTS: White subjects with low education and black subjects with high education had twice the risk of dementia of white subjects with high education (95\% confidence interval (CI)=1.5-2.4 and 95\% CI=1.4-2.7); black subjects with low education had five times the risk of dementia (95\% CI=3.4-7.7). Likewise, for subjects with low 3MSE scores, black subjects had 6.7 times the risk of dementia (95\% CI=4.7-9.7) and white subjects had 2.7 times the risk of dementia (95\% CI=2.2-3.5) as white subjects with high 3MSE scores. Finally, in Cox models, there was no significant black-white difference in dementia risk after adjustment for all confounders and baseline 3MSE.

CONCLUSION: Black race was associated with greater dementia risk even after adjustment for education and other potential confounders. This black-white difference in dementia risk was markedly attenuated after adjustment for baseline cognitive screening scores. The apparent race effect may reflect gaps in the quality of education or differences in the trajectory of impaired cognitive function experienced by the two groups. Future investigations might take these findings into consideration for the design of studies evaluating black-white differences in dementia risk.

}, keywords = {African Continental Ancestry Group, Aged, Cognition, Dementia, Educational Status, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Psychological Tests, Retrospective Studies, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2006.00747.x}, author = {Shadlen, Marie-Florence and Siscovick, David and Fitzpatrick, Annette L and Dulberg, Corinne and Kuller, Lewis H and Jackson, Sharon} } @article {908, title = {Kidney function predicts the rate of bone loss in older individuals: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {61}, year = {2006}, month = {2006 Jul}, pages = {743-8}, abstract = {

BACKGROUND: Results of cross-sectional analyses of the association of kidney function with bone mineral density (BMD) have been conflicting. We examined the association of cystatin-C, a new marker of kidney function that is unrelated to lean mass, with initial and follow-up BMD, in an ancillary study of the Cardiovascular Health Study, a population-based cohort of individuals > or = 65 years old.

METHODS: Two years after measurement of cystatin-C and other covariates, the first BMD was measured in Pittsburgh, Pennsylvania and Davis, California, by using dual energy x-ray absorptiometry. Follow-up BMD was measured in Pittsburgh 4 years later. Associations of cystatin-C with initial BMD and the change in BMD (\%/y) at the hip were examined with linear regression. Analyses were conducted separately for men and women.

RESULTS: In 1519 participants who had cystatin-C and initial BMD assessed, 614 had follow-up BMD. The percent annual change in BMD at the total hip by cystatin-C quartiles was -0.24, -0.13, -0.40, and -0.66\%/y (first to fourth quartile) in women and -0.02, -0.30, -0.18, and -0.94\%/y in men. After adjusting for potential confounders, cystatin-C was marginally associated with initial BMD in men but not women. Cystatin-C was associated with bone loss in men; after adjustment for weight loss, cystatin-C was not associated with bone loss in women.

CONCLUSION: Kidney dysfunction, as assessed by cystatin-C, is associated with a more rapid loss of BMD at the hip, especially in men. Further studies are needed to confirm these findings and to determine whether this loss leads to an elevated risk of fracture.

}, keywords = {Absorptiometry, Photon, Aged, Bone Density, Creatinine, Cystatin C, Cystatins, Female, Hip, Humans, Kidney Diseases, Kidney Function Tests, Linear Models, Longitudinal Studies, Male, Osteoporosis, Predictive Value of Tests}, issn = {1079-5006}, doi = {10.1093/gerona/61.7.743}, author = {Fried, Linda F and Shlipak, Michael G and Stehman-Breen, Catherine and Mittalhenkle, Anuja and Seliger, Stephen and Sarnak, Mark and Robbins, John and Siscovick, David and Harris, Tamara B and Newman, Anne B and Cauley, Jane A} } @article {933, title = {Association of kidney function with incident hip fracture in older adults.}, journal = {J Am Soc Nephrol}, volume = {18}, year = {2007}, month = {2007 Jan}, pages = {282-6}, abstract = {

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95\% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95\% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95\% CI 1.01, 1.33) but not in men (HR 1.14; 95\% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

}, keywords = {Aged, Aged, 80 and over, Cystatin C, Cystatins, Female, Hip Fractures, Humans, Kidney, Kidney Failure, Chronic, Longitudinal Studies, Male, Osteoporosis, Prospective Studies, Risk Factors, Sex Factors}, issn = {1046-6673}, doi = {10.1681/ASN.2006050546}, author = {Fried, Linda F and Biggs, Mary Louise and Shlipak, Michael G and Seliger, Stephen and Kestenbaum, Bryan and Stehman-Breen, Catherine and Sarnak, Mark and Siscovick, David and Harris, Tamara and Cauley, Jane and Newman, Anne B and Robbins, John} } @article {937, title = {Association of physical activity with sleep-disordered breathing.}, journal = {Sleep Breath}, volume = {11}, year = {2007}, month = {2007 Sep}, pages = {149-57}, abstract = {

This study was performed to determine whether there is a protective association between participation in vigorous or vigorous/moderately vigorous physical activity and the prevalence of sleep-disordered breathing (SDB). Polysomnographic and questionnaire data from the baseline examination of 4,275 participants in the Sleep Heart Health Study (SHHS) were analyzed in relation to information on amount of physical activity and other potentially relevant factors collected from five SHHS parent cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, Strong Heart Study, and Tucson Epidemiologic Study of Airways Obstructive Diseases). Logistic regression models were fitted to determine if amount and strenuousness of physical activity was associated with the presence of SDB. At least 3 h per week of vigorous physical activity reduced the odds of SDB, defined as a respiratory disturbance index (RDI) of at least 15 apneas/hypopneas per hour (Adjusted OR, 0.68; 95\%CI, 0.51-0.91). A qualitatively similar but slightly weaker association was observed when SDB was defined as a RDI > or = 10 per hour (Adjusted OR, 0.81; 95\%CI, 0.64-1.02). These findings remained after adjustment for sleepiness and restricting analyses to participants with good health. Three or more hours of moderately vigorous or vigorous physical activity also appeared to confer some protection against SDB, but these associations were weaker. Gender- and obesity-stratified analyses suggested that the protective association between physical activity and SDB occurred primarily in men and those who were obese. A program of regular vigorous physical activity of at least 3 h per week may be a useful adjunctive treatment modality for SDB, but this association needs confirmation with a prospective clinical trial.

}, keywords = {Adult, Cardiac Rehabilitation, Cardiovascular Diseases, Cohort Studies, Exercise, Female, Humans, Longitudinal Studies, Male, Middle Aged, Obesity, Polysomnography, Pulmonary Disease, Chronic Obstructive, Pulmonary Ventilation, Risk Factors, Sex Factors, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Sleep Stages, Weight Loss}, issn = {1520-9512}, doi = {10.1007/s11325-006-0095-5}, author = {Quan, Stuart F and O{\textquoteright}Connor, George T and Quan, Jason S and Redline, Susan and Resnick, Helaine E and Shahar, Eyal and Siscovick, David and Sherrill, Duane L} } @article {961, title = {Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {167}, year = {2007}, month = {2007 Apr 23}, pages = {802-7}, abstract = {

BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus.

METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681).

RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95\% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95\% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95\% confidence interval, 1.1-2.3]).

CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.

}, keywords = {Aged, Body Mass Index, C-Reactive Protein, Depression, Diabetes Mellitus, Type 2, Drinking, Female, Humans, Longitudinal Studies, Male, Smoking}, issn = {0003-9926}, doi = {10.1001/archinte.167.8.802}, author = {Carnethon, Mercedes R and Biggs, Mary L and Barzilay, Joshua I and Smith, Nicholas L and Vaccarino, Viola and Bertoni, Alain G and Arnold, Alice and Siscovick, David} } @article {1015, title = {Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study.}, journal = {Clin J Am Soc Nephrol}, volume = {3}, year = {2008}, month = {2008 Mar}, pages = {450-6}, abstract = {

BACKGROUND AND OBJECTIVES: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries.

RESULTS: Acute renal failure developed in 225 (3.9\%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness.

CONCLUSIONS: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.

}, keywords = {Acute Kidney Injury, Aged, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.02610607}, author = {Mittalhenkle, Anuja and Stehman-Breen, Catherine O and Shlipak, Michael G and Fried, Linda F and Katz, Ronit and Young, Bessie A and Seliger, Stephen and Gillen, Daniel and Newman, Anne B and Psaty, Bruce M and Siscovick, David} } @article {1013, title = {Cystatin C and aging success.}, journal = {Arch Intern Med}, volume = {168}, year = {2008}, month = {2008 Jan 28}, pages = {147-53}, abstract = {

BACKGROUND: To our knowledge, the effect of kidney function on successful aging has not been examined.

METHODS: We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged >or= 65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability.

RESULTS: A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m(2), respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27\% (95\% confidence interval, 11\%-39\%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95\% confidence interval, 1.00-1.98).

CONCLUSION: A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.

}, keywords = {Aged, Aging, Biomarkers, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney, Male}, issn = {0003-9926}, doi = {10.1001/archinternmed.2007.40}, author = {Sarnak, Mark J and Katz, Ronit and Fried, Linda F and Siscovick, David and Kestenbaum, Brian and Seliger, Stephen and Rifkin, Dena and Tracy, Russell and Newman, Anne B and Shlipak, Michael G} } @article {1045, title = {Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {118}, year = {2008}, month = {2008 Aug 19}, pages = {800-7}, abstract = {

BACKGROUND: Vigorous exertion and endurance training have been reported to increase atrial fibrillation (AF). Associations of habitual light or moderate activity with AF incidence have not been evaluated.

METHODS AND RESULTS: We prospectively investigated associations of leisure-time activity, exercise intensity, and walking habits, assessed at baseline and updated during follow-up visits, with incident AF, diagnosed by annual 12-lead ECGs and hospital discharge records, from 1989 to 2001 among 5446 adults > or =65 years of age in the Cardiovascular Health Study. During 47 280 person-years of follow-up, 1061 new AF cases occurred (incidence 22.4/1000 person-years). In multivariable-adjusted analyses, leisure-time activity was associated with lower AF incidence in a graded manner, with 25\% (hazard ratio [HR] 0.75, 95\% confidence interval [CI] 0.61 to 0.90), 22\% (HR 0.78, 95\% CI 0.65 to 0.95), and 36\% (HR 0.64, 95\% CI 0.52 to 0.79) lower risk in quintiles 3, 4, and 5 versus quintile 1 (P for trend <0.001). Exercise intensity had a U-shaped relationship with AF (quadratic P=0.02): Versus no exercise, AF incidence was lower with moderate-intensity exercise (HR 0.72, 95\% CI 0.58 to 0.89) but not with high-intensity exercise (HR 0.87, 95\% CI 0.64 to 1.19). Walking distance and pace were each associated with lower AF risk in a graded manner (P for trend <0.001); when we assessed the combined effects of distance and pace, individuals in quartiles 2, 3, and 4 had 25\% (HR 0.75, 95\% CI 0.56 to 0.99), 32\% (HR 0.68, 95\% CI 0.50 to 0.92), and 44\% (HR 0.56, 95\% CI 0.38 to 0.82) lower AF incidence than individuals in quartile 1. Findings appeared unrelated to confounding by comorbidity or indication. After evaluation of cut points of moderate leisure-time activity (approximately 600 kcal/week), walking distance (12 blocks per week), and pace (2 mph), 26\% of all new AF cases (95\% CI 7\% to 43\%) appeared attributable to absence of these activities.

CONCLUSIONS: Light to moderate physical activities, particularly leisure-time activity and walking, are associated with significantly lower AF incidence in older adults.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Exercise, Female, Humans, Incidence, Leisure Activities, Male, Motor Activity, Prospective Studies, Walking}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.108.785626}, author = {Mozaffarian, Dariush and Furberg, Curt D and Psaty, Bruce M and Siscovick, David} } @article {1062, title = {Rapid kidney function decline and mortality risk in older adults.}, journal = {Arch Intern Med}, volume = {168}, year = {2008}, month = {2008 Nov 10}, pages = {2212-8}, abstract = {

BACKGROUND: Impaired kidney function is associated with increased mortality risk in older adults. It remains unknown, however, whether longitudinal declines in kidney function are independently associated with increased cardiovascular and all-cause mortality in older adults.

METHODS: The Cardiovascular Health Study evaluated a cohort of community-dwelling older adults enrolled from 1989 to 1993 in 4 US communities with follow-up through 2005. Among 4380 participants, the slope of annual decline in estimated glomerular filtration rate (eGFR) was estimated using both serum creatinine (eGFR(creat)) and cystatin C (eGFR(cys)) rates, which were measured at baseline, year 3, and year 7 of follow-up. Rapid decline in eGFR was defined as a loss greater than 3 mL/min/1.73 m(2) per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up.

RESULTS: Mean (SD) levels of creatinine and cystatin C were 0.93 (0.30) mg/dL and 1.03 (0.25) mg/L, respectively; mean (SD) eGFR(creat) and eGFR(cys) were 79 (23) mL/min/1.73 m(2) and 79 (19) mL/min/1.73 m(2), respectively. Individuals with rapid decline measured by eGFR(creat) (n = 714; 16\%) had increased risk of cardiovascular (adjusted hazard ratio [AHR], 1.70; 95\% confidence interval [CI], 1.40-2.06) and all-cause (AHR, 1.73; 95\% CI, 1.54-1.94) mortality. Individuals with rapid decline measured by eGFR(cys) (n = 1083; 25\%) also had increased risk of cardiovascular (AHR, 1.53; 95\% CI, 1.29-1.80) and all-cause (AHR, 1.53; 95\% CI, 1.38-1.69) mortality. The association of rapid decline in eGFR with elevated mortality risk did not differ across subgroups based on baseline kidney function, age, sex, race, or prevalent coronary heart disease.

CONCLUSION: Rapid decline in eGFR is associated with an increased risk of cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables.

}, keywords = {Aged, Cardiovascular Diseases, Creatinine, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Mortality}, issn = {1538-3679}, doi = {10.1001/archinte.168.20.2212}, author = {Rifkin, Dena E and Shlipak, Michael G and Katz, Ronit and Fried, Linda F and Siscovick, David and Chonchol, Michel and Newman, Anne B and Sarnak, Mark J} } @article {1007, title = {The relationship between exercise and risk of venous thrombosis in elderly people.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Mar}, pages = {517-22}, abstract = {

OBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.

DESIGN: Observational study with a median follow-up of 11.6 years.

SETTING: The Cardiovascular Health Study in four U.S. communities.

PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).

MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.

RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95\% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95\% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95\% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95\% CI=1.08-2.83) than no exercise at all.

CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.

}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Energy Metabolism, Exercise, Female, Humans, Male, Prevalence, Risk Factors, United States, Venous Thrombosis}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01588.x}, author = {van Stralen, Karlijn J and Doggen, Carine J M and Lumley, Thomas and Cushman, Mary and Folsom, Aaron R and Psaty, Bruce M and Siscovick, David and Rosendaal, Frits R and Heckbert, Susan R} } @article {1057, title = {Clinical and subclinical cardiovascular disease and kidney function decline in the elderly.}, journal = {Atherosclerosis}, volume = {204}, year = {2009}, month = {2009 May}, pages = {298-303}, abstract = {

OBJECTIVE: Kidney function decline in elderly persons may be the result of microvascular atherosclerosis. As a proxy for the renovascular system, we evaluated the association of clinical and subclinical cardiovascular disease (CVD) with kidney function decline.

METHODS: This study included 4380 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged >or=65 from 4 U.S. communities. Creatinine and cystatin C were measured at baseline, year 3, and year 7; eligible subjects had at least two measures. Creatinine-based estimated glomerular filtration rate (eGFR(creat)) was calculated using the MDRD equation. Rapid kidney function decline was defined as an annual eGFR loss >3 mL/min/1.73 m(2). Predictors of rapid kidney decline included prevalent and subclinical measures of CVD.

RESULTS: Mean decline in eGFR(creat) was 0.4+/-2.6/year; 714 (16\%) had rapid progression. In multivariate models adjusted for demographics, cardiovascular risk factors, and inflammation, prevalent stroke (OR, 95\% CI: 1.55, 1.16-2.08) and heart failure (OR, 95\% CI: 1.80, 1.40-2.31) were independent predictors of rapid kidney decline. Among persons without clinical CV, the subclinical disease measures ankle-arm index <0.9 (OR, 95\% CI: 1.67, 1.25-2.24), common carotid intima-media thickness (>or=1.14 mm) (OR, 95\% CI: 1.52, 1.12-2.06) and internal carotid intima-media thickness (>1.82 mm) (OR, 95\% CI: 1.50, 1.12-2.02) had independent associations with rapid kidney function decline. Results were similar using cystatin C.

CONCLUSION: Clinical atherosclerosis and heart failure and subclinical measures of CVD have independent associations with kidney function decline progression in the elderly, suggesting an underlying role of renal atherosclerosis.

}, keywords = {Age Factors, Aged, Atherosclerosis, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Failure, Humans, Kidney, Kidney Diseases, Linear Models, Longitudinal Studies, Male, Odds Ratio, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2008.08.016}, author = {Shlipak, Michael G and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda F and Siscovick, David and Sarnak, Mark J} } @article {1095, title = {Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {169}, year = {2009}, month = {2009 Apr 27}, pages = {798-807}, abstract = {

BACKGROUND: The combined impact of lifestyle factors on incidence of diabetes mellitus later in life is not well established. The objective of this study was to determine how lifestyle factors, assessed in combination, relate to new-onset diabetes in a broad and relatively unselected population of older adults.

METHODS: We prospectively examined associations of lifestyle factors, measured using repeated assessments later in life, with incident diabetes mellitus during a 10-year period (1989-1998) among 4883 men and women 65 years or older (mean [SD] age at baseline, 73 [6] years) enrolled in the Cardiovascular Health Study. Low-risk lifestyle groups were defined by physical activity level (leisure-time activity and walking pace) above the median; dietary score (higher fiber intake and polyunsaturated to saturated fat ratio, lower trans-fat intake and lower mean glycemic index) in the top 2 quintiles; never smoked or former smoker more than 20 years ago or for fewer than 5 pack-years; alcohol use (predominantly light or moderate); body mass index less than 25 (calculated as weight in kilograms divided by height in meters squared); and waist circumference of 88 cm for women or 92 cm for men. The main outcome measure was incident diabetes defined annually by new use of insulin or oral hypoglycemic medications. We also evaluated fasting and 2-hour postchallenge glucose levels.

RESULTS: During 34,539 person-years, 337 new cases of drug-treated diabetes mellitus occurred (9.8 per 1000 person-years). After adjustment for age, sex, race, educational level, and annual income, each lifestyle factor was independently associated with incident diabetes. Overall, the rate of incident diabetes was 35\% lower (relative risk, 0.65; 95\% confidence interval, 0.59-0.71) for each 1 additional lifestyle factor in the low-risk group. Participants whose physical activity level and dietary, smoking, and alcohol habits were all in the low-risk group had an 82\% lower incidence of diabetes (relative risk, 0.18; 95\% confidence interval, 0.06-0.56) compared with all other participants. When absence of adiposity (either body mass index <25 or waist circumference < or =88/92 cm for women/men) was added to the other 4 low-risk lifestyle factors, incidence of diabetes was 89\% lower (relative risk, 0.11; 95\% confidence interval, 0.01-0.76). Overall, 9 of 10 new cases of diabetes appeared to be attributable to these 5 lifestyle factors. Associations were slightly attenuated, but still highly significant, for incident diabetes defined by medication use or glucose level.

CONCLUSION: Even later in life, combined lifestyle factors are associated with a markedly lower incidence of new-onset diabetes mellitus.

}, keywords = {Age of Onset, Aged, Aged, 80 and over, Diabetes Mellitus, Type 2, Female, Humans, Incidence, Life Style, Male, National Heart, Lung, and Blood Institute (U.S.), Prospective Studies, Risk Factors, United States}, issn = {1538-3679}, doi = {10.1001/archinternmed.2009.21}, author = {Mozaffarian, Dariush and Kamineni, Aruna and Carnethon, Mercedes and Djouss{\'e}, Luc and Mukamal, Kenneth J and Siscovick, David} } @article {1099, title = {Multiple loci associated with indices of renal function and chronic kidney disease.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {712-7}, abstract = {

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 {\texttimes} 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

}, keywords = {Chromosome Mapping, Cohort Studies, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Meta-Analysis as Topic, Mucoproteins, Netherlands, Polymorphism, Single Nucleotide, Prevalence, Uromodulin}, issn = {1546-1718}, doi = {10.1038/ng.377}, author = {K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Hwang, Shih-Jen and Katz, Ronit and Li, Man and Yang, Qiong and Gudnason, Vilmundur and Launer, Lenore J and Harris, Tamara B and Smith, Albert V and Arking, Dan E and Astor, Brad C and Boerwinkle, Eric and Ehret, Georg B and Ruczinski, Ingo and Scharpf, Robert B and Chen, Yii-Der Ida and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Sarnak, Mark and Siscovick, David and Benjamin, Emelia J and Levy, Daniel and Upadhyay, Ashish and Aulchenko, Yurii S and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Chasman, Daniel I and Par{\'e}, Guillaume and Ridker, Paul M and Kao, W H Linda and Witteman, Jacqueline C and Coresh, Josef and Shlipak, Michael G and Fox, Caroline S} } @article {1148, title = {Physical activity and rapid decline in kidney function among older adults.}, journal = {Arch Intern Med}, volume = {169}, year = {2009}, month = {2009 Dec 14}, pages = {2116-23}, abstract = {

BACKGROUND: Habitual physical activity (PA) has both physiologic and metabolic effects that may moderate the risk of kidney function decline. We tested the hypothesis that higher levels of PA are associated with a lower risk of kidney function decline using longitudinal data from a large cohort of older adults.

METHODS: We studied 4011 ambulatory participants aged 65 or older from the Cardiovascular Health Study (CHS) who completed at least 2 measurements of kidney function over 7 years. We calculated a PA score (range, 2-8) by summing kilocalories expended per week (ordinal score of 1-5 from quintiles of kilocalories per week) and walking pace (ordinal score for categories of <2, 2-3, and >3 mph). Rapid decline in kidney function decline (RDKF) was defined by loss of more than 3.0 mL/min/1.73 m(2) per year in glomerular filtration rate, which we estimated by using longitudinal measurements of cystatin C levels.

RESULTS: A total of 958 participants had RDKF (23.9\%; 4.1 events per 100 person-years). The estimated risk of RDKF was 16\% in the highest PA group (score of 8) and 30\% in the lowest PA group (score of 2). After multivariate adjustment, we found that the 2 highest PA groups (scores of 7-8) were associated with a 28\% lower risk of RDKF (95\% confidence interval, 21\%-41\% lower risk) than the 2 lowest PA groups (score of 2-3). Greater kilocalories of leisure-time PA and walking pace were also each associated with a lower incidence of RDKF.

CONCLUSION: Higher levels of PA are associated with a lower risk of RDKF among older adults.

}, keywords = {Aged, Cystatin C, Female, Glomerular Filtration Rate, Humans, Kidney Function Tests, Longitudinal Studies, Male, Motor Activity, Renal Insufficiency, Time Factors}, issn = {1538-3679}, doi = {10.1001/archinternmed.2009.438}, author = {Robinson-Cohen, Cassianne and Katz, Ronit and Mozaffarian, Dariush and Dalrymple, Lorien S and de Boer, Ian and Sarnak, Mark and Shlipak, Mike and Siscovick, David and Kestenbaum, Bryan} } @article {1144, title = {Rapid decline of kidney function increases cardiovascular risk in the elderly.}, journal = {J Am Soc Nephrol}, volume = {20}, year = {2009}, month = {2009 Dec}, pages = {2625-30}, abstract = {

Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C-based estimated GFR as >3 ml/min per 1.73 m(2)/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24\%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95\% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95\% CI 1.21 to 1.83), and PAD (HR 1.67; 95\% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95\% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Failure, Humans, Longitudinal Studies, Male, Myocardial Infarction, Peripheral Vascular Diseases, Renal Insufficiency, Chronic, Risk Factors, Stroke, Time Factors, United States}, issn = {1533-3450}, doi = {10.1681/ASN.2009050546}, author = {Shlipak, Michael G and Katz, Ronit and Kestenbaum, Bryan and Siscovick, David and Fried, Linda and Newman, Anne and Rifkin, Dena and Sarnak, Mark J} } @article {1128, title = {Age and cystatin C in healthy adults: a collaborative study.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 Feb}, pages = {463-9}, abstract = {

BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.

METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46\% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).

CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

}, keywords = {Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Cystatin C, Humans, Kidney, Middle Aged, Reference Values}, issn = {1460-2385}, doi = {10.1093/ndt/gfp474}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Katz, Ronit and Fried, Linda F and Newman, Anne B and Canada, Robert B and Harris, Tamara and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {1207, title = {Diabetes and coronary heart disease as risk factors for mortality in older adults.}, journal = {Am J Med}, volume = {123}, year = {2010}, month = {2010 Jun}, pages = {556.e1-9}, abstract = {

BACKGROUND: Type 2 diabetes has been described as a coronary heart disease (CHD) "risk equivalent." We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common.

METHODS: The Cardiovascular Health Study is a longitudinal study of men and women (n=5784) aged > or =65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose > or =7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization.

RESULTS: Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95\% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent=8.4\%) and prevalent CHD (6.7\%) was similar in women, but the proportion of mortality attributable to CHD (16.5\%) as compared with diabetes (6.4\%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95\% CI, 0.75-0.96) as compared with those who had diabetes alone.

CONCLUSIONS: Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.

}, keywords = {Aged, Coronary Disease, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Male, Prevalence, Risk Factors, Sex Distribution, Survival Rate, Time Factors, United States}, issn = {1555-7162}, doi = {10.1016/j.amjmed.2009.11.023}, author = {Carnethon, Mercedes R and Biggs, Mary L and Barzilay, Joshua and Kuller, Lewis H and Mozaffarian, Dariush and Mukamal, Kenneth and Smith, Nicholas L and Siscovick, David} } @article {1203, title = {Egg consumption and risk of type 2 diabetes in older adults.}, journal = {Am J Clin Nutr}, volume = {92}, year = {2010}, month = {2010 Aug}, pages = {422-7}, abstract = {

BACKGROUND: Type 2 diabetes (T2D) remains an important public health issue in the United States. There are limited and inconsistent data on the association between egg consumption and fasting glucose or incident diabetes.

OBJECTIVES: We assessed the association between egg intake and incident diabetes in older adults.

DESIGN: In this prospective study of 3898 men and women from the Cardiovascular Health Study (1989-2007), we assessed egg consumption by using a picture-sorted food questionnaire and ascertained incident T2D annually by using information on hypoglycemic agents and plasma glucose. We used Cox proportional hazards models to estimate adjusted relative risks.

RESULTS: During a mean follow-up of 11.3 y, 313 new cases of T2D occurred. Crude incidence rates of T2D were 7.39, 6.83, 7.00, 6.72, and 12.20 per 1000 person-years in people who reported egg consumption of never, <1 egg/mo, 1-3 eggs/mo, 1-4 eggs/wk, and almost daily, respectively. In multivariable-adjusted models, there was no association between egg consumption and increased risk of T2D in either sex and overall. In a secondary analysis, dietary cholesterol was not associated with incident diabetes (P for trend = 0.47). In addition, egg consumption was not associated with clinically meaningful differences in fasting glucose, fasting insulin, or measures of insulin resistance despite small absolute analytic differences that were significant.

CONCLUSION: In this cohort of older adults with limited egg intake, there was no association between egg consumption or dietary cholesterol and increased risk of incident T2D.

}, keywords = {Aged, Blood Glucose, Cholesterol, Dietary, Diabetes Mellitus, Type 2, Diet, Diet Surveys, Eggs, Feeding Behavior, Female, Humans, Insulin, Insulin Resistance, Male, Proportional Hazards Models, Prospective Studies, Risk Factors, Surveys and Questionnaires}, issn = {1938-3207}, doi = {10.3945/ajcn.2010.29406}, author = {Djouss{\'e}, Luc and Kamineni, Aruna and Nelson, Tracy L and Carnethon, Mercedes and Mozaffarian, Dariush and Siscovick, David and Mukamal, Kenneth J} } @article {1183, title = {New loci associated with kidney function and chronic kidney disease.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 May}, pages = {376-84}, abstract = {

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

}, keywords = {Cohort Studies, Creatinine, Cystatin C, Diet, Europe, Genetic Markers, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Models, Genetic, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.568}, author = {K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Glazer, Nicole L and Parsa, Afshin and Gao, Xiaoyi and Yang, Qiong and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Li, Man and Schmidt, Helena and Tanaka, Toshiko and Isaacs, Aaron and Ketkar, Shamika and Hwang, Shih-Jen and Johnson, Andrew D and Dehghan, Abbas and Teumer, Alexander and Par{\'e}, Guillaume and Atkinson, Elizabeth J and Zeller, Tanja and Lohman, Kurt and Cornelis, Marilyn C and Probst-Hensch, Nicole M and Kronenberg, Florian and T{\"o}njes, Anke and Hayward, Caroline and Aspelund, Thor and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Rampersaud, Evadnie and Mitchell, Braxton D and Arking, Dan E and Boerwinkle, Eric and Struchalin, Maksim and Cavalieri, Margherita and Singleton, Andrew and Giallauria, Francesco and Metter, Jeffrey and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Siscovick, David and Psaty, Bruce M and Zillikens, M Carola and Oostra, Ben A and Feitosa, Mary and Province, Michael and de Andrade, Mariza and Turner, Stephen T and Schillert, Arne and Ziegler, Andreas and Wild, Philipp S and Schnabel, Renate B and Wilde, Sandra and Munzel, Thomas F and Leak, Tennille S and Illig, Thomas and Klopp, Norman and Meisinger, Christa and Wichmann, H-Erich and Koenig, Wolfgang and Zgaga, Lina and Zemunik, Tatijana and Kolcic, Ivana and Minelli, Cosetta and Hu, Frank B and Johansson, Asa and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and Schreiber, Stefan and Aulchenko, Yurii S and Felix, Janine F and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Imboden, Medea and Nitsch, Dorothea and Brandst{\"a}tter, Anita and Kollerits, Barbara and Kedenko, Lyudmyla and M{\"a}gi, Reedik and Stumvoll, Michael and Kovacs, Peter and Boban, Mladen and Campbell, Susan and Endlich, Karlhans and V{\"o}lzke, Henry and Kroemer, Heyo K and Nauck, Matthias and V{\"o}lker, Uwe and Polasek, Ozren and Vitart, Veronique and Badola, Sunita and Parker, Alexander N and Ridker, Paul M and Kardia, Sharon L R and Blankenberg, Stefan and Liu, Yongmei and Curhan, Gary C and Franke, Andre and Rochat, Thierry and Paulweber, Bernhard and Prokopenko, Inga and Wang, Wei and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Shlipak, Michael G and van Duijn, Cornelia M and Borecki, Ingrid and Kr{\"a}mer, Bernhard K and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Witteman, Jacqueline C and Pramstaller, Peter P and Rettig, Rainer and Hastie, Nick and Chasman, Daniel I and Kao, W H and Heid, Iris M and Fox, Caroline S} } @article {1336, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Sep}, pages = {e1002292}, abstract = {

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Chronic Disease, Creatinine, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Association Studies, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Epidermal Growth Factor, Uromodulin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002292}, author = {B{\"o}ger, Carsten A and Gorski, Mathias and Li, Man and Hoffmann, Michael M and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O{\textquoteright}Seaghdha, Conall M and Kutalik, Zolt{\'a}n and Wichmann, H-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andre and Hofman, Albert and Beckmann, Jacques S and Kr{\"a}mer, Bernhard K and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I and Heid, Iris M and Fox, Caroline S and Kao, W H} } @article {1340, title = {Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Oct 31}, pages = {8514-9}, abstract = {

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 {\texttimes} 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 {\texttimes} 10(-7)) and rs17501108 (P = 9.9 {\texttimes} 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 7, Corneal Topography, Enzyme-Linked Immunosorbent Assay, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hepatocyte Growth Factor, Humans, Keratoconus, Middle Aged, Nucleic Acid Hybridization, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Tagged Sites}, issn = {1552-5783}, doi = {10.1167/iovs.11-8261}, author = {Burdon, Kathryn P and Macgregor, Stuart and Bykhovskaya, Yelena and Javadiyan, Sharhbanou and Li, Xiaohui and Laurie, Kate J and Muszynska, Dorota and Lindsay, Richard and Lechner, Judith and Haritunians, Talin and Henders, Anjali K and Dash, Durga and Siscovick, David and Anand, Seema and Aldave, Anthony and Coster, Douglas J and Szczotka-Flynn, Loretta and Mills, Richard A and Iyengar, Sudha K and Taylor, Kent D and Phillips, Tony and Montgomery, Grant W and Rotter, Jerome I and Hewitt, Alex W and Sharma, Shiwani and Rabinowitz, Yaron S and Willoughby, Colin and Craig, Jamie E} } @article {1230, title = {Chronic kidney disease and the risk of end-stage renal disease versus death.}, journal = {J Gen Intern Med}, volume = {26}, year = {2011}, month = {2011 Apr}, pages = {379-85}, abstract = {

BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.

OBJECTIVE: To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.

DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.

PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.

MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.

KEY RESULTS: During 9.7 years of follow-up, 5\% of the cohort progressed to ESRD, and 61\% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.

CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Cohort Studies, Female, Follow-Up Studies, Humans, Kidney Failure, Chronic, Longitudinal Studies, Male, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors, Treatment Outcome}, issn = {1525-1497}, doi = {10.1007/s11606-010-1511-x}, author = {Dalrymple, Lorien S and Katz, Ronit and Kestenbaum, Bryan and Shlipak, Michael G and Sarnak, Mark J and Stehman-Breen, Catherine and Seliger, Stephen and Siscovick, David and Newman, Anne B and Fried, Linda} } @article {1256, title = {Cystatin C identifies chronic kidney disease patients at higher risk for complications.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Jan}, pages = {147-55}, abstract = {

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9\% had CKD by the creatinine-based equation only, 2\% had CKD by the cystatin C-based equation only, and 4\% had CKD by both equations; in CHS, these percentages were 12, 4, and 13\%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95\% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95\% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95\% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95\% CI 0.98 to 1.21), 1.78 (95\% CI 1.53 to 2.08), and 1.74 (95\% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Chronic Disease, Creatinine, Cystatin C, Disease Progression, Female, Glomerular Filtration Rate, Heart Failure, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Risk Factors}, issn = {1533-3450}, doi = {10.1681/ASN.2010050483}, author = {Peralta, Carmen A and Katz, Ronit and Sarnak, Mark J and Ix, Joachim and Fried, Linda F and de Boer, Ian and Palmas, Walter and Siscovick, David and Levey, Andrew S and Shlipak, Michael G} } @article {1306, title = {Electrocardiographic and clinical predictors separating atherosclerotic sudden cardiac death from incident coronary heart disease.}, journal = {Heart}, volume = {97}, year = {2011}, month = {2011 Oct}, pages = {1597-601}, abstract = {

OBJECTIVE: To identify specific ECG and clinical predictors that separate atherosclerotic sudden cardiac death (SCD) from incident coronary heart disease (CHD) (non-fatal events and non-sudden death) in the combined cohorts of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study.

METHODS: This analysis included 18,497 participants (58\% females, 24\% black individuals, mean age 58 years) who were initially free of clinical CHD. A competing risk analysis was conducted to examine the prognostic significance of baseline clinical characteristics and an extensive electronic database of ECG measurements for prediction of 229 cases of SCD as a first event versus 2297 incident CHD cases (2122 non-fatal events and 175 non-sudden death) that occurred during a median follow-up time of 13 years in the Cardiovascular Health Study and 14 years in the Atherosclerosis Risk in Communities study.

RESULTS: After adjusting for common CHD risk factors, a number of clinical characteristics and ECG measurements were independently predictive of SCD and CHD. However, the risk of SCD versus incident CHD was significantly different for race/ethnicity, hypertension, body mass index (BMI), heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2. Black race/ethnicity (compared to non-black) was predictive of high SCD risk but less risk of incident CHD (p value for differences in the risk (HR) for SCD versus CHD <0.0001). Hypertension, increased heart rate, prolongation of QTc and abnormally inverted T wave were stronger predictors of high SCD risk compared to CHD (p value=0.0460, 0.0398, 0.0158 and 0.0265, respectively). BMI was not predictive of incident CHD but was predictive of high SCD risk in a quadratic fashion (p value=0.0220). On the other hand, elevated ST height as measured at the J point and that measured at 60 ms after the J point in V2 were not predictive of SCD but were predictive of high incident CHD risk (p value=0.0251 and 0.0155, respectively).

CONCLUSIONS: SCD and CHD have many risk factors in common. Hypertension, race/ethnicity, BMI, heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2 have the potential to separate between the risks of SCD and CHD. These results need to be validated in another cohort.

}, keywords = {Adult, Aged, Aged, 80 and over, Body Mass Index, Continental Population Groups, Coronary Disease, Death, Sudden, Cardiac, Electrocardiography, Ethnic Groups, Female, Heart Rate, Humans, Hypertension, Male, Middle Aged, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Risk Adjustment, Risk Factors, Time Factors, United States}, issn = {1468-201X}, doi = {10.1136/hrt.2010.215871}, author = {Soliman, Elsayed Z and Prineas, Ronald J and Case, L Douglas and Russell, Gregory and Rosamond, Wayne and Rea, Thomas and Sotoodehnia, Nona and Post, Wendy S and Siscovick, David and Psaty, Bruce M and Burke, Gregory L} } @article {1327, title = {Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Sep}, pages = {e1002264}, abstract = {

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3{\texttimes}10(-7)) and FNDC1 (p-value = 3.0{\texttimes}10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6{\texttimes}10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

}, keywords = {Adaptor Proteins, Vesicular Transport, Adult, African Continental Ancestry Group, Aged, Animals, Female, Gene Knockdown Techniques, Genetic Association Studies, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, KCNQ1 Potassium Channel, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Neoplasm Proteins, Phenotype, Polymorphism, Single Nucleotide, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002264}, author = {Liu, Ching-Ti and Garnaas, Maija K and Tin, Adrienne and K{\"o}ttgen, Anna and Franceschini, Nora and Peralta, Carmen A and de Boer, Ian H and Lu, Xiaoning and Atkinson, Elizabeth and Ding, Jingzhong and Nalls, Michael and Shriner, Daniel and Coresh, Josef and Kutlar, Abdullah and Bibbins-Domingo, Kirsten and Siscovick, David and Akylbekova, Ermeg and Wyatt, Sharon and Astor, Brad and Mychaleckjy, Josef and Li, Man and Reilly, Muredach P and Townsend, Raymond R and Adeyemo, Adebowale and Zonderman, Alan B and de Andrade, Mariza and Turner, Stephen T and Mosley, Thomas H and Harris, Tamara B and Rotimi, Charles N and Liu, Yongmei and Kardia, Sharon L R and Evans, Michele K and Shlipak, Michael G and Kramer, Holly and Flessner, Michael F and Dreisbach, Albert W and Goessling, Wolfram and Cupples, L Adrienne and Kao, W Linda and Fox, Caroline S} } @article {1305, title = {Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Oct 15}, pages = {4056-68}, abstract = {

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 {\texttimes} 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 {\texttimes} 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 {\texttimes} 10(-32)) and SLC22A12 (P= 2.1 {\texttimes} 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 {\texttimes} 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

}, keywords = {Adult, African Americans, Aged, Animals, CHO Cells, Cricetinae, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Gout, Humans, Loss of Heterozygosity, Male, Middle Aged, Organic Anion Transporters, Organic Cation Transport Proteins, Polymorphism, Single Nucleotide, Uric Acid, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddr307}, author = {Tin, Adrienne and Woodward, Owen M and Kao, Wen Hong Linda and Liu, Ching-Ti and Lu, Xiaoning and Nalls, Michael A and Shriner, Daniel and Semmo, Mariam and Akylbekova, Ermeg L and Wyatt, Sharon B and Hwang, Shih-Jen and Yang, Qiong and Zonderman, Alan B and Adeyemo, Adebowale A and Palmer, Cameron and Meng, Yan and Reilly, Muredach and Shlipak, Michael G and Siscovick, David and Evans, Michele K and Rotimi, Charles N and Flessner, Michael F and K{\"o}ttgen, Michael and Cupples, L Adrienne and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1324, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orr{\`u}, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, Stephanie and DeStefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and Jarvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1350, title = {Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study.}, journal = {Hypertension}, volume = {58}, year = {2011}, month = {2011 Dec}, pages = {1021-8}, abstract = {

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD >=20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH >=65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7\% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95\% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.

}, keywords = {Aged, Cardiovascular Diseases, Comorbidity, Death, Sudden, Cardiac, Diabetes Mellitus, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Kidney, Male, Middle Aged, Minerals, Parathyroid Hormone, Proportional Hazards Models, Risk Factors, Socioeconomic Factors, United States, Vitamin D}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.111.179135}, author = {Deo, Rajat and Katz, Ronit and Shlipak, Michael G and Sotoodehnia, Nona and Psaty, Bruce M and Sarnak, Mark J and Fried, Linda F and Chonchol, Michel and de Boer, Ian H and Enquobahrie, Daniel and Siscovick, David and Kestenbaum, Bryan} } @article {5862, title = {Apolipoprotein E and kidney function in older adults.}, journal = {Clin Nephrol}, volume = {78}, year = {2012}, month = {2012 Sep}, pages = {174-80}, abstract = {

BACKGROUND: Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).

METHODS: Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.

RESULTS: Mean eGFRcreat was 72 ml/min/1.73 m2 (25\% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95\% confidence interval (CI) 0.79 (0.67 - 0.93) per allele, fully adjusted OR (95\% CI) 0.80 (0.68 - 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.

CONCLUSIONS: The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.

}, keywords = {Aged, Aged, 80 and over, Alleles, Apolipoproteins E, Confidence Intervals, Creatinine, Cross-Sectional Studies, Cystatin C, Disease Progression, European Continental Ancestry Group, Female, Gene Frequency, Genotype, Glomerular Filtration Rate, Humans, Kidney, Male, Odds Ratio, Renal Insufficiency, Chronic, Risk Factors}, issn = {0301-0430}, author = {Seshasai, Rebecca Kurnik and Katz, Ronit and de Boer, Ian H and Siscovick, David and Shlipak, Michael G and Rifkin, Dena E and Sarnak, Mark J} } @article {1341, title = {Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.}, journal = {Eur Heart J}, volume = {33}, year = {2012}, month = {2012 Jan}, pages = {238-51}, abstract = {

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 {\texttimes} 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 {\texttimes} 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Coronary Artery Disease, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Phospholipases A2, Polymorphism, Single Nucleotide}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehr372}, author = {Grallert, Harald and Dupuis, Jos{\'e}e and Bis, Joshua C and Dehghan, Abbas and Barbalic, Maja and Baumert, Jens and Lu, Chen and Smith, Nicholas L and Uitterlinden, Andr{\'e} G and Roberts, Robert and Khuseyinova, Natalie and Schnabel, Renate B and Rice, Kenneth M and Rivadeneira, Fernando and Hoogeveen, Ron C and Fontes, Jo{\~a}o Daniel and Meisinger, Christa and Keaney, John F and Lemaitre, Rozenn and Aulchenko, Yurii S and Vasan, Ramachandran S and Ellis, Stephen and Hazen, Stanley L and van Duijn, Cornelia M and Nelson, Jeanenne J and M{\"a}rz, Winfried and Schunkert, Heribert and McPherson, Ruth M and Stirnadel-Farrant, Heide A and Psaty, Bruce M and Gieger, Christian and Siscovick, David and Hofman, Albert and Illig, Thomas and Cushman, Mary and Yamamoto, Jennifer F and Rotter, Jerome I and Larson, Martin G and Stewart, Alexandre F R and Boerwinkle, Eric and Witteman, Jacqueline C M and Tracy, Russell P and Koenig, Wolfgang and Benjamin, Emelia J and Ballantyne, Christie M} } @article {1554, title = {Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.}, journal = {JAMA}, volume = {308}, year = {2012}, month = {2012 Nov 14}, pages = {1898-905}, abstract = {

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95\% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95\% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95\% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

}, keywords = {25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Aged, Chronic Disease, Cohort Studies, Female, Genetic Variation, Genotype, Hip Fractures, Humans, Low Density Lipoprotein Receptor-Related Protein-2, Male, Meta-Analysis as Topic, Myocardial Infarction, Neoplasms, Polymorphism, Single Nucleotide, Receptors, Calcitriol, Receptors, Cell Surface, Risk, Steroid Hydroxylases, Vitamin D, Vitamin D3 24-Hydroxylase}, issn = {1538-3598}, doi = {10.1001/jama.2012.17304}, author = {Levin, Gregory P and Robinson-Cohen, Cassianne and de Boer, Ian H and Houston, Denise K and Lohman, Kurt and Liu, Yongmei and Kritchevsky, Stephen B and Cauley, Jane A and Tanaka, Toshiko and Ferrucci, Luigi and Bandinelli, Stefania and Patel, Kushang V and Hagstr{\"o}m, Emil and Micha{\"e}lsson, Karl and Melhus, H{\r a}kan and Wang, Thomas and Wolf, Myles and Psaty, Bruce M and Siscovick, David and Kestenbaum, Bryan} } @article {1555, title = {A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Jan 15}, pages = {421-9}, abstract = {

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 {\texttimes} 10(-8), 2.4 {\texttimes} 10(-7) and 3.1 {\texttimes} 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 {\texttimes} 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 {\texttimes} 10(-5) and 2.6 {\texttimes} 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 {\texttimes} 10(-7) (unadjusted P= 1.2 {\texttimes} 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

}, keywords = {Case-Control Studies, Chromosomes, Human, Pair 2, Cohort Studies, Corneal Transplantation, Developed Countries, Genome-Wide Association Study, Humans, Keratoconus, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddr460}, author = {Li, Xiaohui and Bykhovskaya, Yelena and Haritunians, Talin and Siscovick, David and Aldave, Anthony and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Rotter, Jerome I and Taylor, Kent D and Rabinowitz, Yaron S} } @article {1407, title = {The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Eur Heart J}, volume = {33}, year = {2012}, month = {2012 Nov}, pages = {2709-17}, abstract = {

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.

METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6\%) and 568 (27.1\%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.

CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.

}, keywords = {Aged, Atrial Fibrillation, Body Height, Epidemiologic Methods, Female, Humans, Male, Sex Factors, United States}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehs301}, author = {Rosenberg, Michael A and Patton, Kristen K and Sotoodehnia, Nona and Karas, Maria G and Kizer, Jorge R and Zimetbaum, Peter J and Chang, James D and Siscovick, David and Gottdiener, John S and Kronmal, Richard A and Heckbert, Susan R and Mukamal, Kenneth J} } @article {1395, title = {Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {60}, year = {2012}, month = {2012 Jul}, pages = {1201-7}, abstract = {

OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians.

DESIGN: Retrospective analysis of prospectively collected data.

SETTING: Community.

PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.

MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.

RESULTS: Mean age of the participants was 85, 64\% were female, 66\% had hypertension, 14\% had diabetes mellitus, and 39\% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (>= 75 mL/min per 1.73 m(2) ) and lowest (<= 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95\% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95\% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95\% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ).

CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .

}, keywords = {Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Chi-Square Distribution, Creatinine, Cystatin C, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney Diseases, Male, Prevalence, Proportional Hazards Models, Retrospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2012.04046.x}, author = {Shastri, Shani and Katz, Ronit and Rifkin, Dena E and Fried, Linda F and Odden, Michelle C and Peralta, Carmen A and Chonchol, Michel and Siscovick, David and Shlipak, Michael G and Newman, Anne B and Sarnak, Mark J} } @article {1543, title = {Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.}, journal = {Invest Ophthalmol Vis Sci}, volume = {53}, year = {2012}, month = {2012 Jun 28}, pages = {4152-7}, abstract = {

PURPOSE: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

METHODS: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.

RESULTS: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3{\texttimes}10(-3) and 7{\texttimes}10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7{\texttimes}10(-3) and 7.7{\texttimes}10(-4), respectively. Meta P values of 4.0{\texttimes}10(-5) and 4.0{\texttimes}10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.

CONCLUSIONS: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

}, keywords = {Case-Control Studies, Cornea, Corneal Topography, DNA, Family, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratoconus, Polymorphism, Genetic, Protein-Lysine 6-Oxidase}, issn = {1552-5783}, doi = {10.1167/iovs.11-9268}, author = {Bykhovskaya, Yelena and Li, Xiaohui and Epifantseva, Irina and Haritunians, Talin and Siscovick, David and Aldave, Anthony and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Taylor, Kent D and Rotter, Jerome I and Rabinowitz, Yaron S} } @article {5849, title = {Adiposity and cognitive decline in the cardiovascular health study.}, journal = {Neuroepidemiology}, volume = {40}, year = {2013}, month = {2013}, pages = {274-81}, abstract = {

BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.

METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.

RESULTS: The final sample was comprised of 2,681 women (57.9\%) and 1,949 men (42.1\%) aged 73 {\textpm} 5.2 and 73.9 {\textpm} 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.

CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

}, keywords = {Adiposity, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cognition Disorders, Electric Impedance, Female, Humans, Male, Risk Factors, Waist Circumference, Waist-Hip Ratio}, issn = {1423-0208}, doi = {10.1159/000345136}, author = {Luchsinger, Jos{\'e} A and Biggs, Mary L and Kizer, Jorge R and Barzilay, Joshua and Fitzpatrick, Annette and Newman, Anne and Longstreth, William T and Lopez, Oscar and Siscovick, David and Kuller, Lewis} } @article {5850, title = {Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.}, journal = {JAMA Intern Med}, volume = {173}, year = {2013}, month = {2013 Jan 14}, pages = {29-35}, abstract = {

BACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.

METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2\% women; and 26.6\% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, >=65 years; 58.2\% women; and 15.4\% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.

RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95\% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95\% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95\% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.

CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

}, keywords = {Aged, Atrial Fibrillation, Cardiovascular Diseases, Death, Sudden, Cardiac, Demography, Ethnic Groups, Female, Humans, Incidence, Male, Middle Aged, Proportional Hazards Models, Risk Assessment, Risk Factors, Sex Factors, United States}, issn = {2168-6114}, doi = {10.1001/2013.jamainternmed.744}, author = {Chen, Lin Y and Sotoodehnia, Nona and B{\r u}zkov{\'a}, Petra and Lopez, Faye L and Yee, Laura M and Heckbert, Susan R and Prineas, Ronald and Soliman, Elsayed Z and Adabag, Selcuk and Konety, Suma and Folsom, Aaron R and Siscovick, David and Alonso, Alvaro} } @article {6071, title = {Cardiomyocyte injury assessed by a highly sensitive troponin assay and sudden cardiac death in the community: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {62}, year = {2013}, month = {2013 Dec 03}, pages = {2112-20}, abstract = {

OBJECTIVES: This study sought to determine the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).

BACKGROUND: The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.

METHODS: Levels of cardiac troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4,431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3,089 subjects. All deaths, including SCD, were adjudicated by a central events committee.

RESULTS: Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD (hazard ratio [HR] for +1 log(hsTnT): 2.04, 95\% confidence interval [CI]: 1.78 to 2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR: 1.30, 95\% CI: 1.05 to 1.62), as well as for incident heart failure and myocardial infarction (HR: 1.26, 95\% CI: 1.01 to 1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [fully adjusted HR: 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT >=12.10 vs. 5.01 to 12.09 vs. <= 5.00 pg/ml, respectively; p trend = 0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (fully adjusted HR for +1 pg/ml per year increase from baseline: 1.03, 95\% CI: 1.01 to 1.06).

CONCLUSIONS: The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.

}, keywords = {Aged, Ambulatory Care, Biomarkers, Death, Sudden, Cardiac, Female, Heart Arrest, Humans, Longitudinal Studies, Male, Middle Aged, Myocardium, Myocytes, Cardiac, Proportional Hazards Models, Risk Assessment, Troponin T}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.07.049}, author = {Hussein, Ayman A and Gottdiener, John S and Bartz, Traci M and Sotoodehnia, Nona and DeFilippi, Christopher and Dickfeld, Timm and Deo, Rajat and Siscovick, David and Stein, Phyllis K and Lloyd-Jones, Donald} } @article {7379, title = {Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults.}, journal = {Atherosclerosis}, volume = {231}, year = {2013}, month = {2013 Nov}, pages = {114-9}, abstract = {

OBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.

METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals >=65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.

RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95\% CI 4.35-9.01] g per doubling of FGF23). 32\% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95\% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95\% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95\% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95\% CI 0.97-1.48]).

CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.

}, keywords = {Aged, Female, Fibroblast Growth Factors, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Longitudinal Studies, Male, Renal Insufficiency, Chronic, Risk Factors, Ultrasonography}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.09.002}, author = {Jovanovich, Anna and Ix, Joachim H and Gottdiener, John and McFann, Kim and Katz, Ronit and Kestenbaum, Bryan and de Boer, Ian H and Sarnak, Mark and Shlipak, Michael G and Mukamal, Kenneth J and Siscovick, David and Chonchol, Michel} } @article {6076, title = {Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.}, journal = {Invest Ophthalmol Vis Sci}, volume = {54}, year = {2013}, month = {2013 Apr 12}, pages = {2696-704}, abstract = {

PURPOSE: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.

METHODS: A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.

RESULTS: Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 {\texttimes} 10(-3) and 7.4 {\texttimes} 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 {\texttimes} 10(-4) (odds ratio [OR] = 1.30) and 2.9 {\texttimes} 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 {\texttimes} 10(-3)).

CONCLUSIONS: SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.

}, keywords = {Adult, Aged, Collagen Type V, Cornea, Corneal Topography, DNA, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratoconus, Male, Microscopy, Acoustic, Middle Aged, Polymorphism, Single Nucleotide, Tomography, Optical Coherence}, issn = {1552-5783}, doi = {10.1167/iovs.13-11601}, author = {Li, Xiaohui and Bykhovskaya, Yelena and Canedo, Ana Laura Caiado and Haritunians, Talin and Siscovick, David and Aldave, Anthony J and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Rotter, Jerome I and Taylor, Kent D and Rabinowitz, Yaron S} } @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 {5854, title = {Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study.}, journal = {Ann Epidemiol}, volume = {23}, year = {2013}, month = {2013 Mar}, pages = {106-11}, abstract = {

PURPOSE: To determine if the associations among established risk factors and reduced kidney function vary by age.

METHODS: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.

RESULTS: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95\% confidence interval [CI], 0.1, 4.4), 5.1 (95\% CI, 4.1, 6.1), and 6.9 (95\%~CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80~years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95\% CI, 3.5, 6.3), 7.1 (95\% CI, 6.0, 8.3), 8.9 (95\% CI, 5.4, 11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.

CONCLUSIONS: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Aging, Causality, Cholesterol, LDL, Cohort Studies, Comorbidity, Cross-Sectional Studies, Cystatin C, Female, Humans, Hypertension, Kidney Function Tests, Male, Netherlands, Obesity, Prevalence, Renal Insufficiency, Chronic, Risk Factors, Smoking, United States}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2012.12.004}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Fried, Linda F and Newman, Anne B and Katz, Ronit and Satterfield, Suzanne and Harris, Tamara B and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {5993, title = {Inflammation and sudden cardiac death in a community-based population of older adults: the Cardiovascular Health Study.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1425-32}, abstract = {

BACKGROUND: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue.

OBJECTIVE: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults.

METHODS: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease.

RESULTS: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95\% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95\% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95\% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95\% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95\% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95\% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95\% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95\% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease.

CONCLUSION: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Female, Humans, Inflammation, Interleukin-6, Male, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.004}, author = {Hussein, Ayman A and Gottdiener, John S and Bartz, Traci M and Sotoodehnia, Nona and DeFilippi, Christopher and See, Vincent and Deo, Rajat and Siscovick, David and Stein, Phyllis K and Lloyd-Jones, Donald} } @article {5875, title = {Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e53830}, abstract = {

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5{\texttimes}10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3{\texttimes}10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1{\texttimes}10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9{\texttimes}10(-6)) and upstream of GLI2 (rs6721654; P = 6.5{\texttimes}10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5{\texttimes}10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

}, keywords = {Apolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3}, issn = {1932-6203}, doi = {10.1371/journal.pone.0053830}, author = {Holliday, Elizabeth G and Smith, Albert V and Cornes, Belinda K and Buitendijk, Gabri{\"e}lle H S and Jensen, Richard A and Sim, Xueling and Aspelund, Thor and Aung, Tin and Baird, Paul N and Boerwinkle, Eric and Cheng, Ching Yu and van Duijn, Cornelia M and Eiriksdottir, Gudny and Gudnason, Vilmundur and Harris, Tamara and Hewitt, Alex W and Inouye, Michael and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore and Li, Xiaohui and Liew, Gerald and Lumley, Thomas and McElduff, Patrick and McKnight, Barbara and Mitchell, Paul and Psaty, Bruce M and Rochtchina, Elena and Rotter, Jerome I and Scott, Rodney J and Tay, Wanting and Taylor, Kent and Teo, Yik Ying and Uitterlinden, Andr{\'e} G and Viswanathan, Ananth and Xie, Sophia and Vingerling, Johannes R and Klaver, Caroline C W and Tai, E Shyong and Siscovick, David and Klein, Ronald and Cotch, Mary Frances and Wong, Tien Y and Attia, John and Wang, Jie Jin} } @article {5845, title = {Insulin resistance and risk of incident heart failure: Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 May}, pages = {364-70}, abstract = {

BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease.

METHODS AND RESULTS: We examined 4425 participants (60\% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95\% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin).

CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction.

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

}, keywords = {Aged, Female, Heart Atria, Heart Failure, Heart Ventricles, Humans, Incidence, Insulin, Insulin Resistance, Male, Middle Aged, Myocardial Infarction, Organ Size, Proportional Hazards Models, Prospective Studies}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.112.000022}, author = {Banerjee, Dipanjan and Biggs, Mary L and Mercer, Laina and Mukamal, Kenneth and Kaplan, Robert and Barzilay, Joshua and Kuller, Lewis and Kizer, Jorge R and Djouss{\'e}, Luc and Tracy, Russell and Zieman, Susan and Lloyd-Jones, Donald and Siscovick, David and Carnethon, Mercedes} } @article {6136, title = {Kidney function and prevalent and incident frailty.}, journal = {Clin J Am Soc Nephrol}, volume = {8}, year = {2013}, month = {2013 Dec}, pages = {2091-9}, abstract = {

BACKGROUND AND OBJECTIVES: Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: CHS enrolled community-dwelling adults age >=65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). Secondary analyses examined eGFR using serum creatinine (eGFR(SCr)). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity.

RESULTS: The mean age was 75 years and the median eGFR(cys) was 73 ml/min per 1.73 m(2). Among participants with an eGFR(cys) <45 ml/min per 1.73 m(2), 24\% had prevalent frailty. In multivariable analysis and compared with eGFR(cys) >=90 ml/min per 1.73 m(2), eGFR(cys) categories of 45-59 (odds ratio [OR], 1.80; 95\% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95\% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95\% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR(cys) categories of 60-75 (incidence rate ratio [IRR], 1.72; 95\% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95\% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95\% CI, 0.90 to 2.60) was not. Lower levels of eGFR(SCr) were not associated with higher risk of prevalent or incident frailty.

CONCLUSIONS: In community-dwelling elders, lower eGFR(cys) was associated with a higher risk of prevalent and incident frailty whereas lower eGFR(SCr) was not. These findings highlight the importance of considering non-GFR determinants of kidney function.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, Creatinine, Cross-Sectional Studies, Cystatin C, Fatigue, Female, Frail Elderly, Geriatric Assessment, Glomerular Filtration Rate, Humans, Incidence, Independent Living, Kidney, Kidney Diseases, Logistic Models, Male, Motor Activity, Multivariate Analysis, Muscle Weakness, Odds Ratio, Phenotype, Prevalence, Prospective Studies, Risk Factors, Time Factors, United States, Weight Loss}, issn = {1555-905X}, doi = {10.2215/CJN.02870313}, author = {Dalrymple, Lorien S and Katz, Ronit and Rifkin, Dena E and Siscovick, David and Newman, Anne B and Fried, Linda F and Sarnak, Mark J and Odden, Michelle C and Shlipak, Michael G} } @article {6078, title = {A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {690-6}, abstract = {

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 {\texttimes} 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 {\texttimes} 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 {\texttimes} 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 {\texttimes} 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

}, keywords = {African Americans, Body Mass Index, Case-Control Studies, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2608}, author = {Monda, Keri L and Chen, Gary K and Taylor, Kira C and Palmer, Cameron and Edwards, Todd L and Lange, Leslie A and Ng, Maggie C Y and Adeyemo, Adebowale A and Allison, Matthew A and Bielak, Lawrence F and Chen, Guanjie and Graff, Mariaelisa and Irvin, Marguerite R and Rhie, Suhn K and Li, Guo and Liu, Yongmei and Liu, Youfang and Lu, Yingchang and Nalls, Michael A and Sun, Yan V and Wojczynski, Mary K and Yanek, Lisa R and Aldrich, Melinda C and Ademola, Adeyinka and Amos, Christopher I and Bandera, Elisa V and Bock, Cathryn H and Britton, Angela and Broeckel, Ulrich and Cai, Quiyin and Caporaso, Neil E and Carlson, Chris S and Carpten, John and Casey, Graham and Chen, Wei-Min and Chen, Fang and Chen, Yii-der I and Chiang, Charleston W K and Coetzee, Gerhard A and Demerath, Ellen and Deming-Halverson, Sandra L and Driver, Ryan W and Dubbert, Patricia and Feitosa, Mary F and Feng, Ye and Freedman, Barry I and Gillanders, Elizabeth M and Gottesman, Omri and Guo, Xiuqing and Haritunians, Talin and Harris, Tamara and Harris, Curtis C and Hennis, Anselm J M and Hernandez, Dena G and McNeill, Lorna H and Howard, Timothy D and Howard, Barbara V and Howard, Virginia J and Johnson, Karen C and Kang, Sun J and Keating, Brendan J and Kolb, Suzanne and Kuller, Lewis H and Kutlar, Abdullah and Langefeld, Carl D and Lettre, Guillaume and Lohman, Kurt and Lotay, Vaneet and Lyon, Helen and Manson, JoAnn E and Maixner, William and Meng, Yan A and Monroe, Kristine R and Morhason-Bello, Imran and Murphy, Adam B and Mychaleckyj, Josyf C and Nadukuru, Rajiv and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Wu, Suh-Yuh and Leske, M Cristina and Neslund-Dudas, Christine and Neuhouser, Marian and Nyante, Sarah and Ochs-Balcom, Heather and Ogunniyi, Adesola and Ogundiran, Temidayo O and Ojengbede, Oladosu and Olopade, Olufunmilayo I and Palmer, Julie R and Ruiz-Narvaez, Edward A and Palmer, Nicholette D and Press, Michael F and Rampersaud, Evandine and Rasmussen-Torvik, Laura J and Rodriguez-Gil, Jorge L and Salako, Babatunde and Schadt, Eric E and Schwartz, Ann G and Shriner, Daniel A and Siscovick, David and Smith, Shad B and Wassertheil-Smoller, Sylvia and Speliotes, Elizabeth K and Spitz, Margaret R and Sucheston, Lara and Taylor, Herman and Tayo, Bamidele O and Tucker, Margaret A and Van Den Berg, David J and Edwards, Digna R Velez and Wang, Zhaoming and Wiencke, John K and Winkler, Thomas W and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yang, James J and Levin, Albert M and Young, Taylor R and Zakai, Neil A and Cushman, Mary and Zanetti, Krista A and Zhao, Jing Hua and Zhao, Wei and Zheng, Yonglan and Zhou, Jie and Ziegler, Regina G and Zmuda, Joseph M and Fernandes, Jyotika K and Gilkeson, Gary S and Kamen, Diane L and Hunt, Kelly J and Spruill, Ida J and Ambrosone, Christine B and Ambs, Stefan and Arnett, Donna K and Atwood, Larry and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Borecki, Ingrid B and Bottinger, Erwin P and Bowden, Donald W and Burke, Gregory and Chanock, Stephen J and Cooper, Richard S and Ding, Jingzhong and Duggan, David and Evans, Michele K and Fox, Caroline and Garvey, W Timothy and Bradfield, Jonathan P and Hakonarson, Hakon and Grant, Struan F A and Hsing, Ann and Chu, Lisa and Hu, Jennifer J and Huo, Dezheng and Ingles, Sue A and John, Esther M and Jordan, Joanne M and Kabagambe, Edmond K and Kardia, Sharon L R and Kittles, Rick A and Goodman, Phyllis J and Klein, Eric A and Kolonel, Laurence N and Le Marchand, Lo{\"\i}c and Liu, Simin and McKnight, Barbara and Millikan, Robert C and Mosley, Thomas H and Padhukasahasram, Badri and Williams, L Keoki and Patel, Sanjay R and Peters, Ulrike and Pettaway, Curtis A and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Rotimi, Charles N and Rybicki, Benjamin A and Sale, Mich{\`e}le M and Schreiner, Pamela J and Signorello, Lisa B and Singleton, Andrew B and Stanford, Janet L and Strom, Sara S and Thun, Michael J and Vitolins, Mara and Zheng, Wei and Moore, Jason H and Williams, Scott M and Ketkar, Shamika and Zhu, Xiaofeng and Zonderman, Alan B and Kooperberg, Charles and Papanicolaou, George J and Henderson, Brian E and Reiner, Alex P and Hirschhorn, Joel N and Loos, Ruth J F and North, Kari E and Haiman, Christopher A} } @article {6546, title = {Dietary protein intake and change in estimated GFR in the Cardiovascular Health Study.}, journal = {Nutrition}, volume = {30}, year = {2014}, month = {2014 Jul-Aug}, pages = {794-9}, abstract = {

OBJECTIVE: With aging, kidney function declines, as evidenced by reduced glomerular filtration rate. It is controversial whether or not high protein intake accelerates this decline. The aim of this study was to determine whether high protein intake was associated with declines in kidney function among older patients.

METHODS: We examined whether dietary protein is associated with change in kidney function (mean follow-up 6.4 y [SD = 1.4, range = 2.5-7.9] in the Cardiovascular Health Study (N = 3623). We estimated protein intake using a food frequency questionnaire and estimated glomerular filtration rate from cystatin C. Associations between protein intake and kidney function were determined by linear and logistic regression models.

RESULTS: Average protein intake was 19\% of energy intake (SD = 5\%). Twenty-seven percent (n = 963) of study participants had rapid decline in kidney function, as defined by (ΔeGFRcysC > 3 mL{\textbullet}min{\textbullet}1.73 m(2)). Protein intake (characterized as g/d and \% energy/d), was not associated with change in estimated glomerular filtration rate (P > 0.05 for all comparisons). There were also no significant associations when protein intake was separated by source (animal and vegetable).

CONCLUSION: These data suggest that higher protein intake does not have a major effect on kidney function decline among elderly men and women.

}, keywords = {Aged, Aging, Diet, Dietary Proteins, Feeding Behavior, Female, Glomerular Filtration Rate, Health, Humans, Kidney, Male, Regression Analysis, Surveys and Questionnaires}, issn = {1873-1244}, doi = {10.1016/j.nut.2013.12.006}, author = {Beasley, Jeannette M and Katz, Ronit and Shlipak, Michael and Rifkin, Dena E and Siscovick, David and Kaplan, Robert} } @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 {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 {6243, title = {Serum carboxymethyl-lysine, disability, and frailty in older persons: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Jun}, pages = {710-6}, abstract = {

BACKGROUND: Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.

METHODS: In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 {\textpm} 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.

RESULTS: Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95\% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95\% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.

CONCLUSIONS: Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML{\textquoteright}s value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Aging, Biomarkers, Cardiac Rehabilitation, Cardiovascular Diseases, Disabled Persons, Female, Follow-Up Studies, Frail Elderly, Health Status, Humans, Incidence, Lysine, Male, Prevalence, Prognosis, Retrospective Studies, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt155}, author = {Whitson, Heather E and Arnold, Alice M and Yee, Laura M and Mukamal, Kenneth J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Siscovick, David and Tracy, Russell P and Thielke, Stephen M and Hirsch, Calvin and Newman, Anne B and Zieman, Susan} } @article {6662, title = {Fibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, volume = {66}, year = {2015}, month = {2015 Jul}, pages = {40-6}, abstract = {

BACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.

STUDY DESIGN: Cohort study.

SETTING \& PARTICIPANTS: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study.

PREDICTOR: Plasma FGF-23 concentrations.

OUTCOMES: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.

MEASUREMENTS: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.

RESULTS: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95\% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95\% CI, 0.85-1.35). In stratified analysis by CKD status (36.5\% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95\% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95\% CI, 0.89-1.62).

LIMITATIONS: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.

CONCLUSIONS: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Death, Sudden, Cardiac, Electrocardiography, Female, Fibroblast Growth Factors, Follow-Up Studies, Heart Arrest, Heart Diseases, Humans, Kaplan-Meier Estimate, Male, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors, Sympathetic Nervous System, United States}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2014.10.025}, author = {Deo, Rajat and Katz, Ronit and de Boer, Ian H and Sotoodehnia, Nona and Kestenbaum, Bryan and Mukamal, Kenneth J and Chonchol, Michel and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G and Ix, Joachim H} } @article {6743, title = {Physical Activity, Physical Fitness, and Leukocyte Telomere Length: The Cardiovascular Health Study.}, journal = {Med Sci Sports Exerc}, volume = {47}, year = {2015}, month = {2015 Dec}, pages = {2525-34}, abstract = {

INTRODUCTION: The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL)--repetitive DNA sequences that may mark biologic aging--is not well-established. Few prior studies (mainly cross-sectional) have been conducted in older adults, and few studies have evaluated PF.

METHODS: We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (mean {\textpm} SD age, 73 {\textpm} 5 yr at baseline) in the Cardiovascular Health Study, with serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL, and changes in cumulatively averaged PA and PF against changes in TL.

RESULTS: Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (P trend = 0.007 and 0.04, respectively). In longitudinal analyses, no significant associations of baseline PA and PF with change in TL were observed. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.

CONCLUSIONS: Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Exercise Test, Female, Hand Strength, Humans, Leukocytes, Male, Motor Activity, Physical Fitness, Prospective Studies, Telomere Homeostasis, Walking}, issn = {1530-0315}, doi = {10.1249/MSS.0000000000000720}, author = {Soares-Miranda, Luisa and Imamura, Fumiaki and Siscovick, David and Jenny, Nancy Swords and Fitzpatrick, Annette L and Mozaffarian, Dariush} } @article {6660, title = {Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.}, journal = {J Am Soc Nephrol}, volume = {26}, year = {2015}, month = {2015 Oct}, pages = {2494-503}, abstract = {

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged >=65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30\% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age ({\textpm}SD) was 78{\textpm}5 years, mean eGFR was 63{\textpm}18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22\% higher odds of CKD progression (adjusted odds ratio, 1.22; 95\% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Disease Progression, Female, Heart Failure, Humans, Kidney Failure, Chronic, Male, Peptide Fragments, Procollagen, Prospective Studies, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2014070696}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth and Djouss{\'e}, Luc and Siscovick, David and Tracy, Russell and Katz, Ronit and Delaney, Joseph A and Chaves, Paulo and Rifkin, Dena E and Hughes-Austin, Jan M and Garimella, Pranav S and Sarnak, Mark J and Shlipak, Michael G and Kizer, Jorge R} } @article {7247, title = {Can a Healthy Lifestyle Compress the Disabled Period in Older Adults?}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Oct}, pages = {1952-1961}, abstract = {

OBJECTIVES: To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life.

DESIGN: Community-based cohort study of older adults followed from 1989 to 2015.

SETTING: Four U.S. communities.

PARTICIPANTS: Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 {\textpm} 5.5, 57\% female, 15.2\% minority) who were not wheelchair dependent and were able to give informed consent at baseline.

MEASUREMENTS: Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL\%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period.

RESULTS: The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95\% confidence interval (CI) = 5.4-9.2) lower YAL/YoL\% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7\% (95\% CI = 1.6-5.9) lower YAL/YoL\% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95\% CI = 0.3-0.8) higher YAL/YoL\%.

CONCLUSION: The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.

}, issn = {1532-5415}, doi = {10.1111/jgs.14314}, author = {Jacob, Mini E and Yee, Laura M and Diehr, Paula H and Arnold, Alice M and Thielke, Stephen M and Chaves, Paulo H M and Gobbo, Liana Del and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {7243, title = {Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population.}, journal = {Circulation}, volume = {134}, year = {2016}, month = {2016 Sep 13}, pages = {806-16}, abstract = {

BACKGROUND: Most sudden cardiac death (SCD) events occur in the general population among persons who do not have any prior history of clinical heart disease. We sought to develop a predictive model of SCD among US adults.

METHODS: We evaluated a series of demographic, clinical, laboratory, electrocardiographic, and echocardiographic measures in participants in the ARIC study (Atherosclerosis Risk in Communities) (n=13 677) and the CHS (Cardiovascular Health Study) (n=4207) who were free of baseline cardiovascular disease. Our initial objective was to derive a SCD prediction model using the ARIC cohort and validate it in CHS. Independent risk factors for SCD were first identified in the ARIC cohort to derive a 10-year risk model of SCD. We compared the prediction of SCD with non-SCD and all-cause mortality in both the derivation and validation cohorts. Furthermore, we evaluated whether the SCD prediction equation was better at predicting SCD than the 2013 American College of Cardiology/American Heart Association Cardiovascular Disease Pooled Cohort risk equation.

RESULTS: There were a total of 345 adjudicated SCD events in our analyses, and the 12 independent risk factors in the ARIC study included age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval. During a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (c-statistic 0.820 in ARIC and 0.745 in CHS). The SCD prediction model was slightly better in predicting SCD than the 2013 American College of Cardiology/American Heart Association Pooled Cohort risk equations (c-statistic 0.808 in ARIC and 0.743 in CHS). Only the SCD prediction model, however, demonstrated similar and accurate prediction for SCD using both the original, uncalibrated score and the recalibrated equation. Finally, in the echocardiographic subcohort, a left ventricular ejection fraction <50\% was present in only 1.1\% of participants and did not enhance SCD prediction.

CONCLUSIONS: Our study is the first to derive and validate a generalizable risk score that provides well-calibrated, absolute risk estimates across different risk strata in an adult population of white and black participants without a clinical diagnosis of cardiovascular disease.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.116.023042}, author = {Deo, Rajat and Norby, Faye L and Katz, Ronit and Sotoodehnia, Nona and Adabag, Selcuk and deFilippi, Christopher R and Kestenbaum, Bryan and Chen, Lin Y and Heckbert, Susan R and Folsom, Aaron R and Kronmal, Richard A and Konety, Suma and Patton, Kristen K and Siscovick, David and Shlipak, Michael G and Alonso, Alvaro} } @article {7125, title = {Echocardiographic Predictors of Sudden Cardiac Death: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study.}, journal = {Circ Cardiovasc Imaging}, volume = {9}, year = {2016}, month = {2016 Aug}, abstract = {

BACKGROUND: This study assessed the echocardiographic predictors of sudden cardiac death (SCD) within 2 population-based cohorts.

METHODS AND RESULTS: Echocardiograms were obtained on 2383 participants (1993-1995) from the ARIC study (Atherosclerosis Risk in Communities; 100\% black) and 5366 participants (1987-1989 and 1994-1995) from the CHS (Cardiovascular Health Study). The main outcome was physician-adjudicated SCD. We used Cox proportional-hazards models with incident coronary heart disease and heart failure as time-dependent covariates to assess the association between echocardiographic variables and SCD, adjusting for Framingham risk score variables, coronary heart disease, and renal function. Cohort-specific results were meta-analyzed. During a median follow-up of 7.3 and 13.1 years, 44 ARIC study participants and 275 CHS participants had SCD, respectively. In the meta-analyzed results, the adjusted hazard ratios (95\% confidence intervals) for predictors of SCD were 3.07 (2.29-4.11) for reduced left ventricular ejection fraction; 1.85 (1.36-2.52) for mitral annular calcification; 1.64 (1.07-2.51) for mitral E/A >1.5, and 1.52 (1.14-2.02) for mitral E/A <0.7 (versus mitral E/A 0.7-1.5); 1.30 (1.15-1.48) per 1 SD increase in left ventricular mass; and 1.15 (1.02-1.30) per 1 SD increase in left atrial diameter. A receiver-operating characteristic model for prediction of SCD using Framingham risk score variables had a C statistic of 0.61 for ARIC study and 0.67 for CHS; the full multivariable model including all echocardiographic variables had a C statistic of 0.76 for ARIC study and 0.74 for CHS.

CONCLUSIONS: In addition to reduced left ventricular ejection fraction, we identified other echocardiographic-derived variables predictive for SCD that provided incremental value compared with clinical risk factors.

}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.115.004431}, author = {Konety, Suma H and Koene, Ryan J and Norby, Faye L and Wilsdon, Tony and Alonso, Alvaro and Siscovick, David and Sotoodehnia, Nona and Gottdiener, John and Fox, Ervin R and Chen, Lin Y and Adabag, Selcuk and Folsom, Aaron R} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7547, title = {The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {102}, year = {2017}, month = {2017 Dec 01}, pages = {4541-4547}, abstract = {

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged >=65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) >=126 mg/dL, non-FPG >=200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare \& Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95\% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Blood Glucose, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Female, Humans, Incidence, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Longitudinal Studies, Male, New England, Prospective Studies, Risk}, issn = {1945-7197}, doi = {10.1210/jc.2017-01273}, author = {Aneke-Nash, Chino S and Xue, XiaoNan and Qi, Qibin and Biggs, Mary L and Cappola, Anne and Kuller, Lewis and Pollak, Michael and Psaty, Bruce M and Siscovick, David and Mukamal, Kenneth and Strickler, Howard D and Kaplan, Robert C} } @article {7601, title = {Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function.}, journal = {J Clin Endocrinol Metab}, volume = {102}, year = {2017}, month = {2017 Apr 01}, pages = {1387-1395}, abstract = {

Context: Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology.

Objective: To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR).

Design, Setting, Participants: Cross-sectional analyses among participants with eGFR >=60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression.

Main Outcome Measure: Serum FGF23.

Results: FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI >=40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2\% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity.

Conclusion: In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.

}, keywords = {Adiposity, Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Fibroblast Growth Factors, Glomerular Filtration Rate, Humans, Kidney, Male, Middle Aged, Minerals, Renal Insufficiency, Chronic, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2016-3563}, author = {Zaheer, Sarah and de Boer, Ian H and Allison, Matthew and Brown, Jenifer M and Psaty, Bruce M and Robinson-Cohen, Cassianne and Michos, Erin D and Ix, Joachim H and Kestenbaum, Bryan and Siscovick, David and Vaidya, Anand} } @article {7579, title = {Genetic loci associated with heart rate variability and their effects on cardiac disease risk.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jun 14}, pages = {15805}, abstract = {

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6\% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74}, issn = {2041-1723}, doi = {10.1038/ncomms15805}, author = {Nolte, Ilja M and Munoz, M Loretto and Tragante, Vinicius and Amare, Azmeraw T and Jansen, Rick and Vaez, Ahmad and von der Heyde, Benedikt and Avery, Christy L and Bis, Joshua C and Dierckx, Bram and van Dongen, Jenny and Gogarten, Stephanie M and Goyette, Philippe and Hernesniemi, Jussi and Huikari, Ville and Hwang, Shih-Jen and Jaju, Deepali and Kerr, Kathleen F and Kluttig, Alexander and Krijthe, Bouwe P and Kumar, Jitender and van der Laan, Sander W and Lyytik{\"a}inen, Leo-Pekka and Maihofer, Adam X and Minassian, Arpi and van der Most, Peter J and M{\"u}ller-Nurasyid, Martina and Nivard, Michel and Salvi, Erika and Stewart, James D and Thayer, Julian F and Verweij, Niek and Wong, Andrew and Zabaneh, Delilah and Zafarmand, Mohammad H and Abdellaoui, Abdel and Albarwani, Sulayma and Albert, Christine and Alonso, Alvaro and Ashar, Foram and Auvinen, Juha and Axelsson, Tomas and Baker, Dewleen G and de Bakker, Paul I W and Barcella, Matteo and Bayoumi, Riad and Bieringa, Rob J and Boomsma, Dorret and Boucher, Gabrielle and Britton, Annie R and Christophersen, Ingrid and Dietrich, Andrea and Ehret, George B and Ellinor, Patrick T and Eskola, Markku and Felix, Janine F and Floras, John S and Franco, Oscar H and Friberg, Peter and Gademan, Maaike G J and Geyer, Mark A and Giedraitis, Vilmantas and Hartman, Catharina A and Hemerich, Daiane and Hofman, Albert and Hottenga, Jouke-Jan and Huikuri, Heikki and Hutri-K{\"a}h{\"o}nen, Nina and Jouven, Xavier and Junttila, Juhani and Juonala, Markus and Kiviniemi, Antti M and Kors, Jan A and Kumari, Meena and Kuznetsova, Tatiana and Laurie, Cathy C and Lefrandt, Joop D and Li, Yong and Li, Yun and Liao, Duanping and Limacher, Marian C and Lin, Henry J and Lindgren, Cecilia M and Lubitz, Steven A and Mahajan, Anubha and McKnight, Barbara and Zu Schwabedissen, Henriette Meyer and Milaneschi, Yuri and Mononen, Nina and Morris, Andrew P and Nalls, Mike A and Navis, Gerjan and Neijts, Melanie and Nikus, Kjell and North, Kari E and O{\textquoteright}Connor, Daniel T and Ormel, Johan and Perz, Siegfried and Peters, Annette and Psaty, Bruce M and Raitakari, Olli T and Risbrough, Victoria B and Sinner, Moritz F and Siscovick, David and Smit, Johannes H and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Staessen, Jan A and Stein, Phyllis K and Stilp, Adrienne M and Stolarz-Skrzypek, Katarzyna and Strauch, Konstantin and Sundstr{\"o}m, Johan and Swenne, Cees A and Syv{\"a}nen, Ann-Christine and Tardif, Jean-Claude and Taylor, Kent D and Teumer, Alexander and Thornton, Timothy A and Tinker, Lesley E and Uitterlinden, Andr{\'e} G and van Setten, Jessica and Voss, Andreas and Waldenberger, Melanie and Wilhelmsen, Kirk C and Willemsen, Gonneke and Wong, Quenna and Zhang, Zhu-Ming and Zonderman, Alan B and Cusi, Daniele and Evans, Michele K and Greiser, Halina K and van der Harst, Pim and Hassan, Mohammad and Ingelsson, Erik and Jarvelin, Marjo-Riitta and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kivimaki, Mika and Kooperberg, Charles and Kuh, Diana and Lehtim{\"a}ki, Terho and Lind, Lars and Nievergelt, Caroline M and O{\textquoteright}Donnell, Chris J and Oldehinkel, Albertine J and Penninx, Brenda and Reiner, Alexander P and Riese, Harri{\"e}tte and van Roon, Arie M and Rioux, John D and Rotter, Jerome I and Sofer, Tamar and Stricker, Bruno H and Tiemeier, Henning and Vrijkotte, Tanja G M and Asselbergs, Folkert W and Brundel, Bianca J J M and Heckbert, Susan R and Whitsel, Eric A and den Hoed, Marcel and Snieder, Harold and de Geus, Eco J C} } @article {7578, title = {Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0186456}, abstract = {

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95\% statistical power to detect a genetic variant associated with effect size of 0.05\% for fish and 0.08\% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

}, keywords = {Adult, Aged, Cohort Studies, Docosahexaenoic Acids, Eicosapentaenoic Acid, Europe, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Seafood, United States}, issn = {1932-6203}, doi = {10.1371/journal.pone.0186456}, author = {Mozaffarian, Dariush and Dashti, Hassan S and Wojczynski, Mary K and Chu, Audrey Y and Nettleton, Jennifer A and M{\"a}nnist{\"o}, Satu and Kristiansson, Kati and Reedik, M{\"a}gi and Lahti, Jari and Houston, Denise K and Cornelis, Marilyn C and van Rooij, Frank J A and Dimitriou, Maria and Kanoni, Stavroula and Mikkil{\"a}, Vera and Steffen, Lyn M and de Oliveira Otto, Marcia C and Qi, Lu and Psaty, Bruce and Djouss{\'e}, Luc and Rotter, Jerome I and Harald, Kennet and Perola, Markus and Rissanen, Harri and Jula, Antti and Krista, Fischer and Mihailov, Evelin and Feitosa, Mary F and Ngwa, Julius S and Xue, Luting and Jacques, Paul F and Per{\"a}l{\"a}, Mia-Maria and Palotie, Aarno and Liu, Yongmei and Nalls, Nike A and Ferrucci, Luigi and Hernandez, Dena and Manichaikul, Ani and Tsai, Michael Y and Kiefte-de Jong, Jessica C and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rallidis, Loukianos and Ridker, Paul M and Rose, Lynda M and Buring, Julie E and Lehtim{\"a}ki, Terho and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Lemaitre, Rozenn and Salomaa, Veikko and Knekt, Paul and Metspalu, Andres and Borecki, Ingrid B and Cupples, L Adrienne and Eriksson, Johan G and Kritchevsky, Stephen B and Bandinelli, Stefania and Siscovick, David and Franco, Oscar H and Deloukas, Panos and Dedoussis, George and Chasman, Daniel I and Raitakari, Olli and Tanaka, Toshiko} } @article {7492, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and Jarvelin, Marjo-Riitta and Johansson, Asa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, Stephanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @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 {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @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 {7990, title = {Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.}, journal = {Diabetes}, volume = {68}, year = {2019}, month = {2019 Feb}, pages = {441-456}, abstract = {

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 {\texttimes} 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 {\texttimes} 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

}, issn = {1939-327X}, doi = {10.2337/db18-0567}, author = {Pollack, Samuela and Igo, Robert P and Jensen, Richard A and Christiansen, Mark and Li, Xiaohui and Cheng, Ching-Yu and Ng, Maggie C Y and Smith, Albert V and Rossin, Elizabeth J and Segr{\`e}, Ayellet V and Davoudi, Samaneh and Tan, Gavin S and Chen, Yii-Der Ida and Kuo, Jane Z and Dimitrov, Latchezar M and Stanwyck, Lynn K and Meng, Weihua and Hosseini, S Mohsen and Imamura, Minako and Nousome, Darryl and Kim, Jihye and Hai, Yang and Jia, Yucheng and Ahn, Jeeyun and Leong, Aaron and Shah, Kaanan and Park, Kyu Hyung and Guo, Xiuqing and Ipp, Eli and Taylor, Kent D and Adler, Sharon G and Sedor, John R and Freedman, Barry I and Lee, I-Te and Sheu, Wayne H-H and Kubo, Michiaki and Takahashi, Atsushi and Hadjadj, Samy and Marre, Michel and Tr{\'e}gou{\"e}t, David-Alexandre and McKean-Cowdin, Roberta and Varma, Rohit and McCarthy, Mark I and Groop, Leif and Ahlqvist, Emma and Lyssenko, Valeriya and Agardh, Elisabet and Morris, Andrew and Doney, Alex S F and Colhoun, Helen M and Toppila, Iiro and Sandholm, Niina and Groop, Per-Henrik and Maeda, Shiro and Hanis, Craig L and Penman, Alan and Chen, Ching J and Hancock, Heather and Mitchell, Paul and Craig, Jamie E and Chew, Emily Y and Paterson, Andrew D and Grassi, Michael A and Palmer, Colin and Bowden, Donald W and Yaspan, Brian L and Siscovick, David and Cotch, Mary Frances and Wang, Jie Jin and Burdon, Kathryn P and Wong, Tien Y and Klein, Barbara E K and Klein, Ronald and Rotter, Jerome I and Iyengar, Sudha K and Price, Alkes L and Sobrin, Lucia} } @article {8616, title = {Associations between neighborhood greenspace and brain imaging measures in non-demented older adults: the Cardiovascular Health Study.}, journal = {Soc Psychiatry Psychiatr Epidemiol}, year = {2021}, month = {2021 Jan 03}, abstract = {

PURPOSE: Greater neighborhood greenspace has been associated with brain health, including better cognition and lower odds of Alzheimer{\textquoteright}s disease in older adults. We investigated associations between neighborhood greenspace and brain-based magnetic resonance imaging (MRI) measures and potential effect modification by sex or apolipoprotein E genotype (APOE), a risk factor for Alzheimer{\textquoteright}s disease.

METHODS: We obtained a sample of non-demented participants 65~years or older (n = 1125) from the longitudinal, population-based Cardiovascular Health Study (CHS). Greenspace data were derived from the National Land Cover Dataset. Adjusted multivariable linear regression estimated associations between neighborhood greenspace five years prior to the MRI and left and right hippocampal volume and 10-point grades of ventricular size and burden of white matter hyperintensity. Interaction terms tested effect modification by APOE genotype and sex. CHS data (1989-1999) were obtained/analyzed in 2020.

RESULTS: Participants were on average 79~years old [standard deviation (SD) = 4], 58\% were female, and 11\% were non-white race. Mean neighborhood greenspace was 38\% (SD = 28\%). Greater proportion of greenspace in the neighborhood five years before MRI was borderline associated with lower ventricle grade (estimate: -~0.30; 95\% confidence interval: -~0.61, 0.00). We observed no associations between greenspace and the other MRI outcome measures and no evidence of effect modification by APOE genotype and sex.

CONCLUSION: This study suggests a possible association between greater greenspace and less ventricular enlargement, a measure reflecting global brain atrophy. If confirmed in other longitudinal cohort studies, interventions and policies to improve community greenspaces may help to maintain brain health in older age.

}, issn = {1433-9285}, doi = {10.1007/s00127-020-02000-w}, author = {Besser, Lilah M and Lovasi, Gina S and Michael, Yvonne L and Garg, Parveen and Hirsch, Jana A and Siscovick, David and Hurvitz, Phil and Biggs, Mary L and Galvin, James E and Bartz, Traci M and Longstreth, W T} } @article {8825, title = {Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, year = {2021}, month = {2021 Aug 07}, abstract = {

PURPOSE: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

METHODS: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

RESULTS: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6~mg/dl) was associated with greater grip strength (kg force) β~=~0.44 [0.16, 0.72]; p~=~0.002) and higher lean muscle mass (kg) (β~=~0.43 [0.08, 0.78]; p~=~0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95\% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p~=~0.65).

CONCLUSION: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.

}, issn = {1532-5415}, doi = {10.1111/jgs.17388}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Shlipak, Michael G and Lyles, Mary F and Bansal, Nisha and Garimella, Pranav S and Ix, Joachim H and Kizer, Jorge R and Strotmeyer, Elsa S and Djouss{\'e}, Luc and Biggs, Mary L and Siscovick, David and Mukamal, Kenneth J} } @article {9153, title = {The Associations of Individual and Subclasses of Non-Esterified Fatty Acids with Disability, and Mobility Limitation in Older Adults: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2022}, month = {2022 Sep 26}, abstract = {

BACKGROUND: We sought to determine the associations between individual non-esterified fatty acids (NEFAs) and disability and mobility limitation.

METHODS: We studied 1734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996-1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per-SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors.

RESULTS: Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation [disability: HR per SD of total NEFA (SD=174.70) =1.11, 95\%CI=1.04-1.18, p=0.001; mobility limitation: HR per SD of total NEFA=1.09, 95\%CI=1.02-1.16, p=0.01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation.

CONCLUSIONS: Higher risks of disability and mobility limitation were observed for pro-inflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs.

}, issn = {1758-535X}, doi = {10.1093/gerona/glac206}, author = {Ahiawodzi, Peter and B{\r u}zkov{\'a}, Petra and Lichtenstein, Alice H and Matthan, Nirupa R and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Arnold, Alice and Newman, Anne B and Siscovick, David and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {9092, title = {Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study.}, journal = {Cardiovasc Diabetol}, volume = {21}, year = {2022}, month = {2022 Jun 20}, pages = {112}, abstract = {

OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.

RESULTS: Mean age for the 2433 included participants was 72.0~years, 33.6\% were male, and 3.7\% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95\% confidence interval = 0.03-0.33).

CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.

}, keywords = {Aged, Cross-Sectional Studies, Female, Glucose, Humans, Insulin Resistance, Male, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1475-2840}, doi = {10.1186/s12933-022-01547-z}, author = {Garg, Parveen K and Biggs, Mary L and Kizer, Jorge R and Shah, Sanjiv J and Psaty, Bruce and Carnethon, Mercedes and Gottdiener, John S and Siscovick, David and Mukamal, Kenneth J} } @article {9025, title = {Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 Mar 01}, pages = {e225012}, abstract = {

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1\% (n = 3) were Asian or Pacific Islander, 4.4\% (n = 183) were Black, 0.3\% (n = 12) were Native American, 95.0\% (n = 3918) were White, and 0.2\% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60\%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4\%]; and 3942 individuals of other races and ethnicitites [95.6\%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95\% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95\% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95\% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95\% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5\% for interleukin 18 to 14.2\% for C-reactive protein, and 16.1\% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Cohort Studies, Dietary Fiber, Female, Humans, Inflammation, Middle Aged, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.5012}, author = {Shivakoti, Rupak and Biggs, Mary L and Djouss{\'e}, Luc and Durda, Peter Jon and Kizer, Jorge R and Psaty, Bruce and Reiner, Alex P and Tracy, Russell P and Siscovick, David and Mukamal, Kenneth J} } @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 {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 {9465, title = {Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts.}, journal = {Res Sq}, year = {2023}, month = {2023 Feb 24}, abstract = {

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of < 5 x 10 , we confirmed association of the signal and found evidence of two additional signals (in and ) within 200 kb of the originally reported signal. Outside of the region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including , , and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

}, doi = {10.21203/rs.3.rs-2073736/v1}, author = {Yang, Chaojie and Veenstra, Jenna and Bartz, Traci and Pahl, Matthew and Hallmark, Brian and Chen, Yii-Der Ida and Westra, Jason and Steffen, Lyn and Brown, Christopher and Siscovick, David and Tsai, Michael and Wood, Alexis and Rich, Stephen and Smith, Caren and O{\textquoteright}Connor, Timothy and Mozaffarian, Dariush and Grant, Struan and Chilton, Floyd and Tintle, Nathan and Lemaitre, Rozenn and Manichaikul, Ani} } @article {9532, title = {Neighborhood greenspace and neighborhood income associated with white matter grade worsening: Cardiovascular Health Study.}, journal = {Alzheimers Dement (Amst)}, volume = {15}, year = {2023}, month = {2023 Oct-Dec}, pages = {e12484}, abstract = {

INTRODUCTION: We examined whether a combined measure of neighborhood greenspace and neighborhood median income was associated with white matter hyperintensity (WMH) and ventricle size changes.

METHODS: The sample included 1260 cognitively normal >= 65-year-olds with two magnetic resonance images (MRI; ≈ 5 years apart). WMH and ventricular size were graded from 0 (least) to 9 (most) abnormal (worsening~=~increase of >=1 grade from initial to follow-up MRI scans). The four-category neighborhood greenspace-income measure was based on median neighborhood greenspace and income values at initial MRI. Multivariable logistic regression tested associations between neighborhood greenspace-income and MRI measures (worsening vs. not).

RESULTS: White matter grade worsening was more likely for those in lower greenspace-lower income neighborhoods than higher greenspace-higher income neighborhoods (odds ratio~=~1.73; 95\% confidence interval~=~1.19-2.51).

DISCUSSION: The combination of lower neighborhood income and lower greenspace may be a risk factor for worsening white matter grade on MRI. However, findings need to be replicated in more diverse cohorts.

HIGHLIGHTS: Population-based cohort of older adults (>= 65 years) with greenspace and MRI dataCombined measure of neighborhood greenspace and neighborhood income at initial MRIMRI outcomes included white matter hyperintensities (WMH) and ventricular sizeLongitudinal change in MRI outcomes measured approximately 5 years apartWorsening WMH over time more likely for lower greenspace-lower income neighborhoods.

}, issn = {2352-8729}, doi = {10.1002/dad2.12484}, author = {Besser, Lilah M and Lovasi, Gina S and Zambrano, Joyce Jimenez and Camacho, Simone and Dhanekula, Devi and Michael, Yvonne L and Garg, Parveen and Hirsch, Jana A and Siscovick, David and Hurvitz, Philip M and Biggs, Mary L and Galvin, James E and Bartz, Traci M and Longstreth, W T} } @article {9284, title = {Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study.}, journal = {Atherosclerosis}, year = {2023}, month = {2023 Jan 29}, abstract = {

BACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons.

METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI.

RESULTS: Mean age was 74.8 years, 59\% were female, and 17\% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95\%CI~=~1.06-2.13, p~=~0.02) across extreme tertiles, and 1.14 (95\%CI~=~0.99-1.31, p~=~0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95\%CI~=~0.69-1.32, p~=~0.76) across extreme tertiles, and 1.03 (95\%CI~=~0.89-1.20, p~=~0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up.

CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.

}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2023.01.020}, author = {Ahiawodzi, Peter and Solaru, Khendi White and Chaves, Paulo H M and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Newman, Anne and Siscovick, David and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @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 {9614, title = {Associations of Neurological Biomarkers in Serum with Gait Measures: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2024}, month = {2024 Feb 09}, abstract = {

BACKGROUND: Gait impairment leads to increased mobility decline and may have neurological contributions. This study explores how neurological biomarkers are related to gait in older adults.

METHODS: We studied participants in the Cardiovascular Health Study, a population-based cohort of older Americans, who underwent a serum biomarker assessment from samples collected in 1996-97 for neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau (n=1959, mean age=78.0 years, 60.8\% female). In a subsample (n=380), cross-sectional associations with quantitative gait measures were explored. This subsample was assessed on a mat for gait speed, step length, double support time, step time, step length variability and step time variability. Gait speed was also measured over a 15-ft walkway annually from 1996-97 to 1998-99, for longitudinal analyses. Linear regression models assessed cross-sectional associations of biomarkers with gait measures, while mixed effects models assessed longitudinal gait speed change from baseline to 1998-99.

RESULTS: NfL was significantly associated with annual gait speed decline (standardized β = -0.64 m/s, 95\% CI: [-1.23, -0.06]) after adjustment for demographic and health factors. Among gait mat-assessed phenotypes, NfL was also cross-sectionally associated with gait speed (β = 0.001 m/s [0.0003, 0.002]) but not with other gait measures. None of the remaining biomarkers were significantly related to gait in either longitudinal or cross-sectional analyses.

CONCLUSION: Higher NfL levels were related to greater annual gait speed decline. Gait speed decline may be related to axonal degeneration. The clinical utility of NfL should be explored.

}, issn = {1758-535X}, doi = {10.1093/gerona/glae043}, author = {Nadkarni, Abhijay and Mukamal, Kenneth J and Zhu, Xiaonan and Siscovick, David and Brach, Jennifer S and Jacob, Mini and Seshadri, Sudha and Abe, Temidayo and Rosano, Caterina and Djouss{\'e}, Luc and Rosso, Andrea L} } @article {9666, title = {Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.}, journal = {Nat Genet}, year = {2024}, month = {2024 Apr 30}, abstract = {

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 {\texttimes} 10) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60\% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95\% CI, 15.5-18.2 mmHg, P = 2.22 {\texttimes} 10) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95\% CI, 5.54-9.70; P = 4.13 {\texttimes} 10) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95\% CI, 0.781-0.801) to 0.826 (95\% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 {\texttimes} 10). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

}, issn = {1546-1718}, doi = {10.1038/s41588-024-01714-w}, author = {Keaton, Jacob M and Kamali, Zoha and Xie, Tian and Vaez, Ahmad and Williams, Ariel and Goleva, Slavina B and Ani, Alireza and Evangelou, Evangelos and Hellwege, Jacklyn N and Yengo, Loic and Young, William J and Traylor, Matthew and Giri, Ayush and Zheng, Zhili and Zeng, Jian and Chasman, Daniel I and Morris, Andrew P and Caulfield, Mark J and Hwang, Shih-Jen and Kooner, Jaspal S and Conen, David and Attia, John R and Morrison, Alanna C and Loos, Ruth J F and Kristiansson, Kati and Schmidt, Reinhold and Hicks, Andrew A and Pramstaller, Peter P and Nelson, Christopher P and Samani, Nilesh J and Risch, Lorenz and Gyllensten, Ulf and Melander, Olle and Riese, Harri{\"e}tte and Wilson, James F and Campbell, Harry and Rich, Stephen S and Psaty, Bruce M and Lu, Yingchang and Rotter, Jerome I and Guo, Xiuqing and Rice, Kenneth M and Vollenweider, Peter and Sundstr{\"o}m, Johan and Langenberg, Claudia and Tobin, Martin D and Giedraitis, Vilmantas and Luan, Jian{\textquoteright}an and Tuomilehto, Jaakko and Kutalik, Zolt{\'a}n and Ripatti, Samuli and Salomaa, Veikko and Girotto, Giorgia and Trompet, Stella and Jukema, J Wouter and van der Harst, Pim and Ridker, Paul M and Giulianini, Franco and Vitart, Veronique and Goel, Anuj and Watkins, Hugh and Harris, Sarah E and Deary, Ian J and van der Most, Peter J and Oldehinkel, Albertine J and Keavney, Bernard D and Hayward, Caroline and Campbell, Archie and Boehnke, Michael and Scott, Laura J and Boutin, Thibaud and Mamasoula, Chrysovalanto and Jarvelin, Marjo-Riitta and Peters, Annette and Gieger, Christian and Lakatta, Edward G and Cucca, Francesco and Hui, Jennie and Knekt, Paul and Enroth, Stefan and de Borst, Martin H and Polasek, Ozren and Concas, Maria Pina and Catamo, Eulalia and Cocca, Massimiliano and Li-Gao, Ruifang and Hofer, Edith and Schmidt, Helena and Spedicati, Beatrice and Waldenberger, Melanie and Strachan, David P and Laan, Maris and Teumer, Alexander and D{\"o}rr, Marcus and Gudnason, Vilmundur and Cook, James P and Ruggiero, Daniela and Kolcic, Ivana and Boerwinkle, Eric and Traglia, Michela and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Johnson, Andrew D and Newton-Cheh, Christopher and Brown, Morris J and Dominiczak, Anna F and Sever, Peter J and Poulter, Neil and Chambers, John C and Elosua, Roberto and Siscovick, David and Esko, T{\~o}nu and Metspalu, Andres and Strawbridge, Rona J and Laakso, Markku and Hamsten, Anders and Hottenga, Jouke-Jan and de Geus, Eco and Morris, Andrew D and Palmer, Colin N A and Nolte, Ilja M and Milaneschi, Yuri and Marten, Jonathan and Wright, Alan and Zeggini, Eleftheria and Howson, Joanna M M and O{\textquoteright}Donnell, Christopher J and Spector, Tim and Nalls, Mike A and Simonsick, Eleanor M and Liu, Yongmei and van Duijn, Cornelia M and Butterworth, Adam S and Danesh, John N and Menni, Cristina and Wareham, Nicholas J and Khaw, Kay-Tee and Sun, Yan V and Wilson, Peter W F and Cho, Kelly and Visscher, Peter M and Denny, Joshua C and Levy, Daniel and Edwards, Todd L and Munroe, Patricia B and Snieder, Harold and Warren, Helen R} } @article {9860, title = {Low-Density Lipoprotein Cholesterol Level Distributions Across Different Ages: Implications for Screening Children for Severe and Familial Hypercholesterolemia.}, journal = {Circulation}, volume = {150}, year = {2024}, month = {2024 Nov 19}, pages = {1741-1744}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.124.069792}, author = {Liu, Junxiu and Bellows, Brandon K and Jacobs, David R and Woo, Jessica G and Urbina, Elaine M and Balte, Pallavi P and Oelsner, Elizabeth C and Kazi, Dhruv S and Siscovick, David and Allen, Norrina B and Rana, Jamal S and Wilkins, John T and Hall, Michael E and Bazzano, Lydia A and Burns, Trudy L and Daniels, Stephen R and Dwyer, Terence and Juonala, Markus and Raitakari, Olli T and Sinaiko, Alan R and Steinberger, Julia and Venn, Alison J and Kartiosuo, Noora and Lehtim{\"a}ki, Terho and Magnussen, Costan G and Viikari, Jorma S A and de Ferranti, Sarah D and Moran, Andrew E and Zhang, Yiyi} } @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} }