@article {749, title = {Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group.}, journal = {Stroke}, volume = {23}, year = {1992}, month = {1992 Dec}, pages = {1752-60}, abstract = {

BACKGROUND AND PURPOSE: This article describes the prevalence of extracranial carotid atherosclerosis assessed by ultrasonography, its association with risk factors, and its relation to symptomatic coronary disease and stroke in men and women aged > or = 65 years.

METHODS: Maximum percent stenosis, maximum common carotid artery wall thickness, and maximum internal carotid artery wall thickness were assessed using duplex ultrasound in 5,201 men and women aged > or = 65 years in the Cardiovascular Health Study, a study of the risk factors and natural history of cardiovascular disease in the elderly. Existing coronary disease and stroke were assessed by physical examination and participant history.

RESULTS: Detectable carotid stenosis was present in 75\% of men and 62\% of women, although the prevalence of > or = 50\% stenosis was low, 7\% in men and 5\% in women. Maximum stenosis and maximum wall thickness measurements increased with age and were uniformly greater at all ages in men than in women (p < 0.00001). Established risk factors for atherosclerosis (hypertension, smoking, diabetes) and indications of vascular disease (left ventricular hypertrophy, major electrocardiographic abnormality, bruits, and history of heart disease or stroke) related to all three carotid artery measures in the elderly. Of the three ultrasound measures, the best correlate for a history of coronary disease was maximum internal carotid artery wall thickness. For stroke the best correlate was common carotid artery wall thickness. Multiple logistic regression models of prevalent coronary heart disease and stroke that included the ultrasound findings indicated, after adjustment for age and sex, that maximum internal wall thickness and maximum common carotid wall thickness were significant correlates of both. Maximum stenosis did not add significantly to the correlation.

CONCLUSIONS: In the elderly the incidence of carotid atherosclerosis was high, although the frequency of severe disease was low. The prevalence and severity of carotid atherosclerosis continued to increase with age even in the late decades of life, and more disease was found in men than in women at all ages. Known risk factors for atherosclerosis continued to relate to carotid abnormalities in the later decades of life, both in symptomatic and asymptomatic subjects.

}, keywords = {Aged, Arteriosclerosis, Cardiomegaly, Carotid Artery Diseases, Cerebrovascular Disorders, Coronary Disease, Female, Humans, Male, Medical Records, Prevalence, Regression Analysis, Risk Factors, Ultrasonography}, issn = {0039-2499}, doi = {10.1161/01.str.23.12.1752}, author = {O{\textquoteright}Leary, D H and Polak, J F and Kronmal, R A and Kittner, S J and Bond, M G and Wolfson, S K and Bommer, W and Price, T R and Gardin, J M and Savage, P J} } @article {747, title = {The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {2}, year = {1992}, month = {1992 Jul}, pages = {509-19}, abstract = {

The Cardiovascular Health Study (CHS) was designed to examine cardiovascular disease and its risk factors in older adults. We report here the distributions of the coagulation factors fibrinogen, factor VII, and factor VIII in a population-based cohort of men and women 65 years or older. In other studies of middle-aged individuals, these factors were shown to be associated with cardiovascular risk. In the CHS cohort, all three factors were elevated, compared to levels reported in middle-aged individuals, and fibrinogen and factor VIII values were higher in each successive age group; factor VII values, in contrast, declined slightly with age in the CHS cohort. Compared to white subjects, blacks had higher values for fibrinogen and factor VIII and lower values for factor VII. While women had markedly higher values for factor VII and factor VIII than men at all ages in the CHS, mean fibrinogen values were not different between men and women.

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Cardiovascular Diseases, Cohort Studies, Factor VII, Factor VIII, Female, Fibrinogen, Humans, Male, Middle Aged, Risk Factors}, issn = {1047-2797}, doi = {10.1016/1047-2797(92)90100-5}, author = {Tracy, R P and Bovill, E G and Fried, L P and Heiss, G and Lee, M H and Polak, J F and Psaty, B M and Savage, P J} } @article {1475, title = {Diabetes mellitus and echocardiographic left ventricular function in free-living elderly men and women: The Cardiovascular Health Study.}, journal = {Am Heart J}, volume = {133}, year = {1997}, month = {1997 Jan}, pages = {36-43}, abstract = {

This report describes the relation among diabetes, blood pressure, and prevalent cardiovascular disease, and echocardiographically measured left ventricular mass and filling (transmitral valve flow) velocities in the Cardiovascular Health Study, a cohort of 5201 men and women > or = 65 years of age. Ventricular septal and left posterior wall thicknesses were greater in diabetic than in nondiabetic subjects, showing a significant linear trend (p = 0.025 for ventricular septal thickness in both sexes combined, p = 0.002 for posterior wall thickness) with increased duration of diabetes. Increased wall thickness of the ventricular septum or the left posterior wall was not associated with prevalent coronary heart disease (CHD) in the cohort. Increased left ventricular mass was associated with diabetic persons not reporting CHD and with all subjects with CHD regardless of glucose tolerance status. After adjusting for body weight, blood pressure, heart rate, and prevalent coronary or cerebrovascular disease, diabetes (as measured by glucose level, insulin use, oral hypoglycemic use, and a positive history of diabetes before baseline examination) remained an independent predictor of increased left ventricular mass among men and women (174.2 gm in diabetic men vs 169.8 gm in normal men, 138.2 gm in diabetic women vs 134.0 gm in normal women, p = 0.043 for both sexes combined). Both early and late diastolic transmitral peak flow velocities were higher with increased duration of diabetes, but the calculated ratio of the early peak flow velocity to the late velocity (E/A ratio) did not differ significantly between subjects with historical diabetes and those with normal fasting glucose (both genders combined, p = 0.190). Glucose level, insulin use, oral hypoglycemic use, and a positive history of diabetes before baseline examination were significant independent predictors of the late transmitral peak flow velocity and its integrated flow-velocity curve but not for the integral of the early peak flow velocity or the E/A ratio. Diabetes is associated with abnormal left ventricular structure and function in elderly persons. This association persists after adjustment for body weight, blood pressure, heart rate, and reported coronary or cerebrovascular disease.

}, keywords = {Aged, Blood Flow Velocity, Blood Pressure, Diabetes Mellitus, Echocardiography, Female, Glucose Tolerance Test, Humans, Male, Mitral Valve, Residence Characteristics, Ventricular Function, Left}, issn = {0002-8703}, author = {Lee, M and Gardin, J M and Lynch, J C and Smith, V E and Tracy, R P and Savage, P J and Szklo, M and Ward, B J} } @article {1478, title = {Dietary assessment using a picture-sort approach.}, journal = {Am J Clin Nutr}, volume = {65}, year = {1997}, month = {1997 Apr}, pages = {1123S-1129S}, abstract = {

Food-frequency questionnaires are usually administered as a list of foods to be checked off by the respondent or interviewer. Techniques in which participants sort into categories cards on which names or pictures of foods are printed can also be used to assess food intake. Food-frequency scores were obtained from a five-category picture sort administered to 4643 men and women aged > or = 65 y in the Cardiovascular Health Study (CHS). This one-step (qualitative) assessment yielded significant associations in expected directions between frequency scores and sex, age, race or ethnicity, body mass index, and use of a special diet. In the two-step (semiquantitative) version of this instrument, an interviewer documented specific frequencies and portion-size information for the foods in each sorting category. A substudy of the two-step version with 96 CHS participants indicated relative validity similar to that of conventionally administered food-frequency questionnaires. The one-step version may be broadly applicable to situations in which general food-pattern data can be informative and cost and time limitations are great. When it is feasible, the two-step picture sort may offer certain methodologic advantages because respondents have a chance to change their responses and the format may simplify the cognitive-response task. Sorting or picture-sort procedures deserve systematic attention in research on dietary assessment methods.

}, keywords = {Aged, Audiovisual Aids, Diet, Female, Food, Humans, Male, Nutrition Assessment, Surveys and Questionnaires}, issn = {0002-9165}, author = {Kumanyika, S K and Tell, G S and Shemanski, L and Martel, J and Chinchilli, V M} } @article {1486, title = {Does the association of risk factors and atherosclerosis change with age? An analysis of the combined ARIC and CHS cohorts. The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) investigators.}, journal = {Stroke}, volume = {28}, year = {1997}, month = {1997 Sep}, pages = {1693-701}, abstract = {

INTRODUCTION: A decrease in the estimated relative risk of cerebrovascular and cardiovascular diseases associated with known disease risk factors has been observed among elderly cohorts, perhaps suggesting that continued risk factor management in the elderly may not be as efficacious as with younger age groups. In this paper, the differential magnitude of the association of risk factors with atherosclerosis across the age spectrum from 45 years to older than 75 years is presented.

METHODS: Subclinical atherosclerosis as measured by carotid ultrasonography and risk factor prevalence were assessed using similar methods among participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study and among participants 65 years and older in the Cardiovascular Health Study (CHS). Pooling these two cohorts provided data on the relationship of risk factors and atherosclerosis on nearly 19,000 participants over a broad age range. Regression analyses were used to assess the consistency of the magnitude of the association of risk factors with atherosclerosis across the age spectrum separately for black and white participants in cross-sectional analyses.

RESULTS: As expected, each of the risk factors was globally (across all ages) associated with increased atherosclerosis. However, the magnitude of the association did not differ across the age spectrum for hypertension, low density lipoprotein cholesterol (LDL-c), fibrinogen, or body mass index (BMI). For whites, there was a significantly greater impact of smoking and HDL-C among older age strata but a smaller impact of diabetes. For black women, the impact of HDL-C decreased among the older age strata.

CONCLUSIONS: These data suggest that most risk factors continue to be associated with increased atherosclerosis at older ages, possibly suggesting a continued value in investigation of strategies to reduce atherosclerosis by controlling risk factors at older ages.

}, keywords = {African Americans, African Continental Ancestry Group, Aged, Aging, Arteriosclerosis, Body Mass Index, Cardiovascular Physiological Phenomena, Cardiovascular System, Carotid Arteries, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, Health Status, Humans, Hypertension, Male, Middle Aged, Regression Analysis, Risk Factors, Sex Factors, Smoking, Tunica Intima, Tunica Media, Ultrasonography}, issn = {0039-2499}, author = {Howard, G and Manolio, T A and Burke, G L and Wolfson, S K and O{\textquoteright}Leary, D H} } @article {1515, title = {Diabetes in older adults: comparison of 1997 American Diabetes Association classification of diabetes mellitus with 1985 WHO classification.}, journal = {Lancet}, volume = {352}, year = {1998}, month = {1998 Sep 26}, pages = {1012-5}, abstract = {

BACKGROUND: We aimed to compare the prevalence of abnormal glucose tolerance identified by the 1985 WHO and the 1997 American Diabetes Association (ADA) diagnostic categories based on information collected in the Cardiovascular Health Study, an epidemiological study of elderly people.

METHODS: We measured glucose concentrations during fasting and 2 h after a 75 g oral glucose-tolerance test in participants aged 65-100 years in the Cardiovascular Health Study. From a 1989 cohort, we analysed the glucose measurements of 4515 individuals without a previous diagnosis of diabetes and of 262 additional measurements from an African-American cohort recruited in 1992-93.

FINDINGS: In the 1989 cohort, the prevalence of untreated diabetes with ADA diagnostic fasting criteria was 7.7\% versus a prevalence of 14.8\% by the WHO criteria. In the African-American cohort, the prevalence of untreated diabetes was 2.7\% with ADA criteria and 11.8\% with WHO criteria. 3509 (77.7\%) of the 4515 participants in the 1989 cohort had normal glucose concentrations according to ADA fasting criteria, compared with 2401 (53.2\%) according to WHO criteria. In the African-American cohort, the corresponding numbers were 239 (91.2\%) versus 153 (58.4\%). All differences in prevalence of abnormal glucose tolerance between ADA and WHO classifications were significant (p<0.0001).

INTERPRETATION: Among elderly individuals, there was a significant difference in the prevalence of diabetes identified by the WHO diagnostic criteria based on oral glucose-tolerance test and the ADA fasting criteria. Consequently, many individuals currently classified as non-diabetic according to ADA criteria would previously have had a diagnosis of diabetes according to WHO criteria. Longitudinal studies are needed to assess the value of the criteria in the identification of individuals at increased risk of diabetes-associated chronic complications.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cohort Studies, Diabetes Mellitus, Female, Glucose Tolerance Test, Humans, Male, Prevalence, Societies, Medical, World Health Organization}, issn = {0140-6736}, doi = {10.1016/S0140-6736(98)04055-0}, author = {Wahl, P W and Savage, P J and Psaty, B M and Orchard, T J and Robbins, J A and Tracy, R P} } @article {1496, title = {Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {18}, year = {1998}, month = {1998 Feb}, pages = {283-93}, abstract = {

A composite measure of subclinical vascular disease has been developed in the Cardiovascular Health Study (CHS). In previous reports, we measured the prevalence of subclinical disease among the original 5201 participants in the CHS, the relationship of risk factors to subclinical disease, and the association of subclinical disease to clinical coronary heart disease. In 1992 to 1993 (year 4 of the study), a larger cohort of 424 black women and 248 black men was added to the study. In this study, we have compared the prevalence of subclinical disease among blacks and whites in the CHS and the association with cardiovascular risk factors. The prevalence of subclinical disease for all participants (aged > or =65 years) was 41.3\% for white women, 39.7\% for black women, 41.9\% for white men, and 43.7\% for black men. The prevalence increased with age. The risk factor associations for subclinical disease were similar among blacks and whites. In multivariate analysis, age, systolic blood pressure, LDL cholesterol, smoking, and family history of myocardial infarction were independently associated with subclinical disease among both black and white women, while for white men, systolic blood pressure, use of antihypertensive medication, smoking, body mass index, and diastolic blood pressure (inverse) were related to subclinical disease. In black men, blood triglyceride level, use of antihypertensive medications, and family history of myocardial infarction (inverse) were associated with subclinical disease.

}, keywords = {African Americans, Aged, Cardiovascular Physiological Phenomena, Cohort Studies, European Continental Ancestry Group, Female, Health Status, Humans, Male, Multivariate Analysis, Prevalence, Regression Analysis, Risk Factors, Vascular Diseases}, issn = {1079-5642}, author = {Kuller, L and Fisher, L and McClelland, R and Fried, L and Cushman, M and Jackson, S and Manolio, T} } @article {610, title = {Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group.}, journal = {J Am Geriatr Soc}, volume = {48}, year = {2000}, month = {2000 Feb}, pages = {115-23}, abstract = {

INTRODUCTION: As part of the baseline examination in the Cardiovascular Health Study, sleep disturbance symptoms including snoring and daytime sleepiness, were assessed as potential risk factors or precipitants of cardiovascular disease (CVD). Because of the association of sleep disturbance with poorer health and the possible associations of sleep apnea with CVD, we hypothesized that those with poorer sleep or daytime sleepiness may be at increased risk of mortality or incident CVD.

SETTING: Participants (n = 5888) were recruited in 1989, with an additional minority cohort recruited in 1993, in four US communities for a cohort study designed to evaluate risk factors for cardiovascular disease.

METHODS: An interview-administered questionnaire regarding health and sleep habits with ongoing ascertainment of total mortality and cardiovascular disease morbidity and mortality, including total CVD morbidity and mortality, incident myocardial infarction, and congestive heart failure.

RESULTS: Daytime sleepiness was the only sleep symptom that was significantly associated with mortality in both men and women. The unadjusted hazard ratio was 2.12 (1.66, 2.72) in women and 1.40 (1.12, 1.73) in men. Men who reported difficulty falling asleep also had an increased mortality rate (HR = 1.43 (1.14, 1.80)) which was not seen in women. The risks were attenuated with adjustment for age but remained significant for daytime sleepiness in women (HR = 1.82 (1.42, 2.34)) and for difficulty falling asleep in men. (HR = 1.29 (1.03, 1.63)). Frequent awakenings, early morning awakening, and snoring were not associated with a significantly increased risk of mortality in these older men and women. Crude event rates were evaluated for total incident cardiovascular morbidity and mortality, incident myocardial infarction, and incident congestive heart failure (CHF). Incident CVD rates were higher in both men and women with daytime sleepiness. The aged adjusted HR was 1.35 (95\% CI = 1.03, 1.76) in men and was 1.66 (95\% CI = 1.28, 2.16) in women. Incident CVD was not higher in those with any other sleep disturbance including snoring. The risk of CVD events associated with daytime sleepiness was attenuated but remained significant in women after adjustment for age. Incident myocardial infarction (MI) rates were also higher in women with daytime sleepiness but were not significantly higher in men. Incident CHF rates were increased in both men and women with daytime sleepiness. In men, the age adjusted HR was 1.49 (95\% CI, 1.12- 1.98) and in women, was 2.21 (95\% CI, 1.64-2.98). Women reporting both daytime sleepiness and frequent awakening had a hazard ratio of 2.34 (95\% CI, 1.66-3.29) for incident CHF compared with those with daytime sleepiness but without frequent awakening. This interaction was not found in men.

CONCLUSIONS: In this study, daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF. These findings were stronger in women than men, i.e., the associations persisted for mortality, CVD, and CHF in women after adjustment for age and other factors. Thus, a report of daytime sleepiness identifies older adults at increased risk for total and cardiovascular mortality, and is an independent risk factor in women.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Female, Health Status, Heart Failure, Humans, Incidence, Male, Multivariate Analysis, Myocardial Infarction, Odds Ratio, Risk Factors, Sex Factors, Sleep Apnea Syndromes, Sleep Stages, Sleep Wake Disorders, Snoring, Surveys and Questionnaires, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2000.tb03901.x}, author = {Newman, A B and Spiekerman, C F and Enright, P and Lefkowitz, D and Manolio, T and Reynolds, C F and Robbins, J} } @article {622, title = {Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group.}, journal = {Circulation}, volume = {102}, year = {2000}, month = {2000 Oct 10}, pages = {1773-9}, abstract = {

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort.

METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40\% and risk of death by 60\% compared with those who had the lowest mean scores.

CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Coronary Disease, Depression, Female, Humans, Male, Prospective Studies, Risk Factors, United States}, issn = {1524-4539}, doi = {10.1161/01.cir.102.15.1773}, author = {Ariyo, A A and Haan, M and Tangen, C M and Rutledge, J C and Cushman, M and Dobs, A and Furberg, C D} } @article {611, title = {Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {20}, year = {2000}, month = {2000 Mar}, pages = {823-9}, abstract = {

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.

}, keywords = {Aged, Arteriosclerosis, Coronary Disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Female, Humans, Incidence, Male, Multivariate Analysis, Myocardial Infarction, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution, Stroke}, issn = {1079-5642}, doi = {10.1161/01.atv.20.3.823}, author = {Kuller, L H and Velentgas, P and Barzilay, J and Beauchamp, N J and O{\textquoteright}Leary, D H and Savage, P J} } @article {623, title = {Does snoring predict sleepiness independently of apnea and hypopnea frequency?}, journal = {Am J Respir Crit Care Med}, volume = {162}, year = {2000}, month = {2000 Oct}, pages = {1512-7}, abstract = {

Obstructive apneas and hypopneas during sleep are a well recognized cause of excessive daytime sleepiness. Snoring is also associated with excess sleepiness, although it is not known whether this reflects an independent effect of snoring or whether snoring is simply a marker for obstructive sleep apnea. To further explore the relation of snoring to sleepiness, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study. The study sample comprises 2,737 men and 3,040 women with a mean age of 64 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Snoring history was obtained via a self-completion questionnaire. The respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, was measured during in-home polysomnography. The ESS score increased progressively with increasing RDI, from a mean of 7.1 (4.2) in subjects with RDI < 1.5 to 8.8 (4.8) in subjects with RDI >/= 15 (p < 0.001). A progressive increase in ESS score was also seen across five categories of snoring frequency, from 6.4 (4.2) in current nonsnorers to 9.3 (4.8) in subjects who snored six to seven nights per week (p < 0.001). The prevalence of excessive daytime sleepiness, defined as an ESS score >/= 11, increased from 15\% in never-snorers to 39\% in those who snored six to seven nights per week. The relation of snoring to sleepiness was seen at all levels of RDI, with no significant change in the relation of snoring to ESS score after adjustment for RDI in multivariate models. The effects of snoring and RDI on sleepiness were little affected by adjustment for age, sex, race, body mass index, or questionnaire evidence of insufficient sleep time or nocturnal leg jerks or cramps. We conclude that both snoring and RDI are independently associated with excess sleepiness in community-dwelling, middle-aged and older adults.

}, keywords = {Adult, Aged, Arousal, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Polysomnography, Risk Factors, Sleep Apnea, Obstructive, Snoring, Wakefulness}, issn = {1073-449X}, doi = {10.1164/ajrccm.162.4.9911073}, author = {Gottlieb, D J and Yao, Q and Redline, S and Ali, T and Mahowald, M W} } @article {727, title = {Diabetes and sleep disturbances: findings from the Sleep Heart Health Study.}, journal = {Diabetes Care}, volume = {26}, year = {2003}, month = {2003 Mar}, pages = {702-9}, abstract = {

OBJECTIVE: To test the hypothesis that diabetes is independently associated with sleep-disordered breathing (SDB), and in particular that diabetes is associated with sleep abnormalities of a central, rather than obstructive, nature.

RESEARCH DESIGN AND METHODS: Using baseline data from the Sleep Heart Health Study (SHHS), we related diabetes to 1). the respiratory disturbance index (RDI; number of apneas plus hypopneas per h of sleep); 2). obstructive apnea index (OAI; >or=3 apneas/h of sleep associated with obstruction of the upper airway); 3). percent of sleep time < 90\% O(2) saturation; 4). central apnea index (CAI; >or=3 apneas [without respiratory effort]/h sleep); 5). occurrence of a periodic breathing (Cheyne Stokes) pattern; and 6) sleep stages. Initial analyses excluding persons with prevalent cardiovascular disease (CVD) were repeated including these participants.

RESULTS: Of the 5874 participants included in this report, 692 (11.8\%) reported diabetes or were taking oral hypoglycemic medications or insulin and 1002 had prevalent CVD. Among the 4872 persons without CVD, 470 (9.6\%) had diabetes. Diabetic participants had worse CVD risk factor profiles than their nondiabetic counterparts, including higher BMI, waist and neck circumferences, triglycerides, higher prevalence of hypertension, and lower HDL cholesterol (P < 0.001, all). Descriptive analyses indicated differences between diabetic and nondiabetic participants in RDI, sleep stages, sleep time <90\% O(2) saturation, CAI, and periodic breathing (P < 0.05, all). However, multivariable regression analyses that adjusted for age, sex, BMI, race, and neck circumference eliminated these differences for all sleep measures except percent time in rapid eye movement (REM) sleep (19.0\% among diabetic vs. 20.1\% among nondiabetic subjects, P < 0.001) and prevalence of periodic breathing (odds ratio [OR] for diabetic subjects versus nondiabetic subjects 1.80, 95\% CI 1.02-3.15). Additionally, adjusted analyses showed diabetes was associated with nonstatistically significant elevations in the odds of an increased central breathing index (OR 1.42, 95\% CI 0.80-2.55). Addition to the analysis of the 1002 persons with prevalent CVD (including 222 people with diabetes) did not materially change these results.

CONCLUSIONS: These data suggest that diabetes is associated with periodic breathing, a respiratory abnormality associated with abnormalities in the central control of ventilation. Some sleep disturbances may result from diabetes through the deleterious effects of diabetes on central control of respiration. The high prevalence of SDB in diabetes, although largely explained by obesity and other confounders, suggests the presence of a potentially treatable risk factor for CVD in the diabetic population.

}, keywords = {Aged, Diabetes Mellitus, Female, Humans, Logistic Models, Male, Middle Aged, Multivariate Analysis, Prevalence, Risk Factors, Sleep Apnea Syndromes, Sleep Apnea, Obstructive}, issn = {0149-5992}, doi = {10.2337/diacare.26.3.702}, author = {Resnick, Helaine E and Redline, Susan and Shahar, Eyal and Gilpin, Adele and Newman, Anne and Walter, Robert and Ewy, Gordon A and Howard, Barbara V and Punjabi, Naresh M} } @article {793, title = {Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.}, journal = {Am J Med}, volume = {117}, year = {2004}, month = {2004 Jul 01}, pages = {19-25}, abstract = {

PURPOSE: To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States.

METHODS: The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review.

RESULTS: The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48\% (175/366) of events. The 28-day case-fatality rate was 11\% (29/265) after a first venous thromboembolism and 25\% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7\% per year (95\% confidence interval [CI]: 4.5\% to 10.9\% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95\% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95\% CI: 2.0 to 41.7).

CONCLUSION: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.

}, keywords = {Aged, Case-Control Studies, Cohort Studies, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Neoplasms, Population Surveillance, Pulmonary Embolism, Recurrence, Risk Factors, Survival Rate, Venous Thrombosis}, issn = {0002-9343}, doi = {10.1016/j.amjmed.2004.01.018}, author = {Cushman, Mary and Tsai, Albert W and White, Richard H and Heckbert, Susan R and Rosamond, Wayne D and Enright, Paul and Folsom, Aaron R} } @article {852, title = {Dementia and Alzheimer{\textquoteright}s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Jul}, pages = {1101-7}, abstract = {

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer{\textquoteright}s disease (AD).

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded.

MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders.

RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95\% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95\% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease.

CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Peripheral Vascular Diseases, Risk Factors}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53360.x}, author = {Newman, Anne B and Fitzpatrick, Annette L and Lopez, Oscar and Jackson, Sharon and Lyketsos, Constantine and Jagust, William and Ives, Diane and DeKosky, Steven T and Kuller, Lewis H} } @article {838, title = {Determinants of vascular dementia in the Cardiovascular Health Cognition Study.}, journal = {Neurology}, volume = {64}, year = {2005}, month = {2005 May 10}, pages = {1548-52}, abstract = {

OBJECTIVE: The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.

METHODS: Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

RESULTS: Approximately 44\% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.

CONCLUSIONS: Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cardiovascular Diseases, Cerebral Arteries, Cerebral Infarction, Cohort Studies, Comorbidity, Continental Population Groups, Dementia, Vascular, Female, Humans, Lateral Ventricles, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Neuropsychological Tests, Risk Factors, Sex Factors}, issn = {1526-632X}, doi = {10.1212/01.WNL.0000160115.55756.DE}, author = {Kuller, L H and Lopez, O L and Jagust, W J and Becker, J T and DeKosky, S T and Lyketsos, C and Kawas, C and Breitner, J C S and Fitzpatrick, A and Dulberg, C} } @article {891, title = {Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study.}, journal = {Arch Gen Psychiatry}, volume = {63}, year = {2006}, month = {2006 Mar}, pages = {273-9}, abstract = {

CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons.

OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease.

DESIGN: Prospective, population-based, longitudinal study.

SETTING: Random sample of adults 65 years or older recruited from 4 US communities.

PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria.

MAIN OUTCOME MEASURE: Diagnosis of MCI.

RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0\%, 13.3\%, and 19.7\% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics.

CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.

}, keywords = {Aged, Cerebrovascular Disorders, Cognition Disorders, Comorbidity, Dementia, Dementia, Vascular, Depressive Disorder, Female, Follow-Up Studies, Geriatric Assessment, Humans, Longitudinal Studies, Male, Prospective Studies, Psychiatric Status Rating Scales, Risk Factors, Sampling Studies, Vascular Diseases}, issn = {0003-990X}, doi = {10.1001/archpsyc.63.3.273}, author = {Barnes, Deborah E and Alexopoulos, George S and Lopez, Oscar L and Williamson, Jeff D and Yaffe, Kristine} } @article {910, title = {Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans.}, journal = {J Am Coll Cardiol}, volume = {48}, year = {2006}, month = {2006 Aug 01}, pages = {478-84}, abstract = {

OBJECTIVES: We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk.

BACKGROUND: Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects.

METHODS: In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories.

RESULTS: Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (-3.2 beats/min, 95\% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95\% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95\% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95\% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95\% CI = 3.3 to 11.9), and 46\% lower likelihood of prolonged QT (relative risk = 0.54, 95\% CI = 0.33 to 0.88).

CONCLUSIONS: These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.

}, keywords = {Aged, Animals, Atrioventricular Node, Cross-Sectional Studies, Diet, Electrocardiography, Fatty Acids, Omega-3, Female, Fishes, Heart, Heart Rate, Humans, Male, Ventricular Function}, issn = {1558-3597}, doi = {10.1016/j.jacc.2006.03.048}, author = {Mozaffarian, Dariush and Prineas, Ronald J and Stein, Phyllis K and Siscovick, David S} } @article {968, title = {Depressive symptoms and age-related macular degeneration in older people: the cardiovascular health study.}, journal = {Ophthalmic Epidemiol}, volume = {14}, year = {2007}, month = {2007 May-Jun}, pages = {127-33}, abstract = {

PURPOSE: To examine the association between age-related macular degeneration (AMD) and depressive symptoms.

METHODS: Population-based, cross-sectional study. A total of 2,194 persons aged 69-97 years were included in the current analyses. During the 1997-1998 examination, retinal photography from one randomly selected eye was graded for presence of early and late AMD using a modified Wisconsin AMD by Grading System. Depressive symptoms were assessed via a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998. Depressive symptoms were defined as a CES-D score of >9 (top quartile of CES-D score) at the 1997-1998 examination.

RESULTS: There were 338 (15.6\%) individuals with early AMD and 29 (1.3\%) with late AMD. Among them, 368 (16.8\%) persons had depressive symptoms at the 1997-1998 examination. Depressive symptoms were not associated with early AMD (multivariable adjusted odds ratio [OR]: 0.97; 95\% confidence intervals [CI]: 0.69-1.36) or late AMD (OR: 1.15; 95\% CI: 0.38-3.46). Including persons using anti-depressive medications did not alter these associations (OR: 0.98; 95\% CI: 0.74-1.32 for early AMD and OR: 0.97; 95\% CI: 0.35-2.67 for late AMD). There was no association in multinomial logistic regression models of increasing quartiles of the CES-D scores with early or late AMD status.

CONCLUSIONS: Our study did not find an association between early AMD and depressive symptoms in older people.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cross-Sectional Studies, Depressive Disorder, Female, Health Surveys, Humans, Intelligence Tests, Macular Degeneration, Male, Photography, United States}, issn = {0928-6586}, doi = {10.1080/09286580601186742}, author = {Sun, Cong and Tikellis, Gabriella and Klein, Ronald and Steffens, David C and Larsen, Emily K Marino and Wong, Tien Y} } @article {992, title = {Depressive symptoms, inflammation, and ischemic stroke in older adults: a prospective analysis in the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {55}, year = {2007}, month = {2007 Nov}, pages = {1825-30}, abstract = {

OBJECTIVES: To investigate the mediator role of inflammation in any relationship between depressive symptoms and ischemic stroke.

DESIGN: Longitudinal prospective study.

SETTING: Review of medical records, death certificates, and the Medicare healthcare utilization database for hospitalizations.

PARTICIPANTS: Total of 5,525 elderly men and women aged 65 and older who were prospectively followed from 1989 to 2000 as participants in the Cardiovascular Health Study.

MEASUREMENTS: Depression symptom scores, inflammatory markers.

RESULTS: Greater depressive symptoms were associated with risk of ischemic stroke (unadjusted hazard ratio (HR)=1.32, 95\% confidence interval (CI)=1.09-1.59; HR=1.26, 95\% CI=1.03-1.54, adjusted for traditional risk factors). When a term for inflammation (C-reactive protein (CRP)) was introduced in the model, the HRs were not appreciably altered (unadjusted HR=1.31, 95\% CI=1.08-1.58; adjusted HR=1.25, 95\% CI=1.02-1.53), indicating that CRP at baseline was not a mediator in this relationship. In analyses stratified according to CRP levels, a J-shaped relationship between depressive symptoms and stroke was evident in the unadjusted analyses; in the fully adjusted model, only CRP in the highest tertile was associated with a higher risk for stroke in the presence of higher depressive symptoms scores.

CONCLUSION: The analyses from this prospective study provide evidence of a positive association between depressive symptoms and risk of incident stroke. Inflammation, as measured according to CRP at baseline, did not appear to mediate the relationship between depressive symptoms and stroke.

}, keywords = {Aged, C-Reactive Protein, Cardiovascular Diseases, Cerebral Infarction, Cohort Studies, Depression, Female, Geriatric Assessment, Humans, Inflammation, Kaplan-Meier Estimate, Longitudinal Studies, Male, Multivariate Analysis, Personality Assessment, Proportional Hazards Models, Prospective Studies, Psychoneuroimmunology, Risk Factors, Socioeconomic Factors, Statistics as Topic, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01393.x}, author = {Arbelaez, Jose J and Ariyo, Abraham A and Crum, Rosa M and Fried, Linda P and Ford, Daniel E} } @article {928, title = {Determinants of serum total and free testosterone levels in women over the age of 65 years.}, journal = {J Clin Endocrinol Metab}, volume = {92}, year = {2007}, month = {2007 Feb}, pages = {509-16}, abstract = {

CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age.

OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women.

DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels.

RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23\% lower total T and 16\% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47\% lower than never users; 4) obese women had 47\% higher total T and 20\% higher free T levels, and overweight women had 24\% higher total T and 14\% higher free T levels, than normal weight women; and 5) free T levels were 51\% higher in black women. Corticosteroid users had 75\% lower total T and 43\% lower free T levels than nonusers.

CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Aging, Body Mass Index, Cross-Sectional Studies, Estrogen Replacement Therapy, Female, Humans, Hypogonadism, Multivariate Analysis, Nonlinear Dynamics, Obesity, Ovariectomy, Ovary, Postmenopause, Predictive Value of Tests, Prevalence, Risk Factors, Testosterone}, issn = {0021-972X}, doi = {10.1210/jc.2006-1399}, author = {Cappola, Anne R and Ratcliffe, Sarah J and Bhasin, Shalender and Blackman, Marc R and Cauley, Jane and Robbins, John and Zmuda, Joseph M and Harris, Tamara and Fried, Linda P} } @article {1052, title = {Diabetes mellitus and gait dysfunction: possible explanatory factors.}, journal = {Phys Ther}, volume = {88}, year = {2008}, month = {2008 Nov}, pages = {1365-74}, abstract = {

BACKGROUND AND OBJECTIVE: Gait characteristics differ in individuals with diabetes compared with those without diabetes. Limited information regarding potential explanatory factors for this association exists. This study examined the association between diabetes and gait characteristics in older adults and explored potential explanatory factors.

DESIGN: A cross-sectional, observational study design was used.

METHODS: At the 1998-1999 clinic visit, 558 ambulatory older adults (mean age=79 years) from the Pittsburgh site of the Cardiovascular Health Study had an assessment of their gait characteristics, diabetes, health status, cognition, mood, lower-extremity circulation and sensation, vision, lower-extremity strength (force-producing capacity), physical activity, and body mass index (BMI). A series of linear regression models were developed to examine the association between diabetes and gait characteristics and to examine potential explanatory factors for the associations.

RESULTS: Diabetes was related to gait speed (beta=-.06 m/s); however, the association was partially explained by health status variables, cognition, mood, lower-extremity circulation and sensation, visual impairment, lower-extremity strength, physical activity, and BMI. Health status and lower-extremity strength each explained the greatest proportion of the association (beta reduced 66\% by each). Diabetes was related to step width (beta=.02 m), and the association could not be explained by the examined factors.

CONCLUSIONS: Diabetes was associated with gait alterations in older adults. Slowed gait speed appears to be secondary to the peripheral effect of the disease on other body systems. The effect of diabetes on step width was not explained in the analyses and may be related to peripheral motor nerve function or central influences of the disease, which could not be assessed in this study.

}, keywords = {Aged, Body Mass Index, Cognition, Cross-Sectional Studies, Diabetes Mellitus, Female, Gait, Geriatric Assessment, Health Status, Humans, Linear Models, Longitudinal Studies, Male, Multicenter Studies as Topic, Muscle Strength}, issn = {1538-6724}, doi = {10.2522/ptj.20080016}, author = {Brach, Jennifer S and Talkowski, Jaime B and Strotmeyer, Elsa S and Newman, Anne B} } @article {1020, title = {Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults.}, journal = {Circulation}, volume = {117}, year = {2008}, month = {2008 Mar 04}, pages = {1130-7}, abstract = {

BACKGROUND: Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.

METHODS AND RESULTS: In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincar{\'e} ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1\% (for difference in standard deviation of normal-to-normal intervals) to 5.9\% and 8.4\% (for differences in Poincar{\'e} ratio and short-term fractal scaling exponent) lower risk.

CONCLUSIONS: Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.

}, keywords = {Aged, Aged, 80 and over, Animals, Cardiovascular Diseases, Cohort Studies, Cross-Sectional Studies, Electrocardiography, Fatty Acids, Omega-3, Female, Fishes, Heart Rate, Humans, Male, Risk Factors, Seafood, Tuna, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.107.732826}, author = {Mozaffarian, Dariush and Stein, Phyllis K and Prineas, Ronald J and Siscovick, David S} } @article {1022, title = {Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 May}, pages = {792-9}, abstract = {

OBJECTIVES: To determine whether high levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp-PLA(2) levels in a community-based cohort of older adults.

DESIGN: Cross-sectional.

SETTING: The Cardiovascular Health Study (CHS), a population-based cohort study of men and women aged 65 and older.

PARTICIPANTS: Five thousand five hundred thirty-one CHS participants.

MEASUREMENTS: Levels of Lp-PLA(2) activity were determined using stored blood samples from the baseline examination.

RESULTS: Mean Lp-PLA(2) was higher in participants with electrocardiographically determined ventricular conduction defect and major Q-wave abnormality and was positively correlated with left ventricular (LV) mass. It was high in those with echocardiographically determined abnormal LV ejection fraction, which persisted after adjustment. Mean Lp-PLA(2) was also higher in participants with mild renal insufficiency and kidney disease. After multivariable adjustment, there was a modest but significant 27\% greater risk of prevalent CHF per standard deviation increment of Lp-PLA(2) and a modest but significant 12\% greater risk of prevalent myocardial infarction. Lp-PLA(2) was weakly but mainly most strongly correlated with cholesterol and lipoproteins, but those correlations were not especially strong. Lp-PLA(2) was weakly positively correlated with soluble intercellular adhesion molecule-1 but not interleukin-6. In total, all factors considered could explain only 29\% of Lp-PLA(2) activity.

CONCLUSION: Novel findings in the study are the associations, in those aged 65 and older, between Lp-PLA(2) activity and LV dysfunction, CHF, and renal disease. CVD risk factors only minimally explain levels of Lp-PLA(2).

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Atherosclerosis, Body Mass Index, Cardiac Output, Low, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Cross-Sectional Studies, Electrocardiography, Female, Heart Failure, Humans, Hypertrophy, Left Ventricular, Long QT Syndrome, Male, Reference Values, Renal Insufficiency, Risk Factors, Statistics as Topic, Triglycerides}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.01667.x}, author = {Furberg, Curt D and Nelson, Jeanenne J and Solomon, Cam and Cushman, Mary and Jenny, Nancy Swords and Psaty, Bruce M} } @article {1118, title = {Depressed mood is not a risk factor for incident dementia in a community-based cohort.}, journal = {Am J Geriatr Psychiatry}, volume = {17}, year = {2009}, month = {2009 Aug}, pages = {653-63}, abstract = {

OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals.

DESIGN: Longitudinal and observational.

SETTING: Community-based cohort study.

PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years).

MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams.

RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood.

CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Dementia, Depression, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status Schedule, Prospective Studies, Psychiatric Status Rating Scales, Residence Characteristics, Risk Factors}, issn = {1545-7214}, author = {Becker, James T and Chang, Yue-Fang and Lopez, Oscar L and Dew, Mary Amanda and Sweet, Robert A and Barnes, Deborah and Yaffe, Kristine and Young, Jeffrey and Kuller, Lewis and Reynolds, Charles F} } @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 {1213, title = {Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.}, journal = {Lancet}, volume = {375}, year = {2010}, month = {2010 Jun 26}, pages = {2215-22}, abstract = {

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.

METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.

FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95\% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10\%, diabetes was estimated to account for 11\% (10-12\%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.

INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.

FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

}, keywords = {Adult, Aged, Blood Glucose, Coronary Disease, Diabetes Complications, Diabetes Mellitus, Fasting, Female, Humans, Male, Middle Aged, Risk Factors, Stroke}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60484-9}, author = {Sarwar, N and Gao, P and Seshasai, S R Kondapally and Gobin, R and Kaptoge, S and Di Angelantonio, E and Ingelsson, E and Lawlor, D A and Selvin, E and Stampfer, M and Stehouwer, C D A and Lewington, S and Pennells, L and Thompson, A and Sattar, N and White, I R and Ray, K K and Danesh, J} } @article {1240, title = {Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Oct 18}, pages = {e13405}, abstract = {

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95\% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83\%). For granulocytes the RR was 1.38 (95\% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95\% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95\% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95\% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95\% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95\% CI: 1.74; 2.75) was attenuated to 1.82 (95\% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

}, keywords = {Adult, Aged, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Leukocyte Count, Male, Middle Aged, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0013405}, author = {Gkrania-Klotsas, Effrossyni and Ye, Zheng and Cooper, Andrew J and Sharp, Stephen J and Luben, Robert and Biggs, Mary L and Chen, Liang-Kung and Gokulakrishnan, Kuppan and Hanefeld, Markolf and Ingelsson, Erik and Lai, Wen-An and Lin, Shih-Yi and Lind, Lars and Lohsoonthorn, Vitool and Mohan, Viswanathan and Muscari, Antonio and Nilsson, Goran and Ohrvik, John and Chao Qiang, Jiang and Jenny, Nancy Swords and Tamakoshi, Koji and Temelkova-Kurktschiev, Theodora and Wang, Ya-Yu and Yajnik, Chittaranjan Sakerlal and Zoli, Marco and Khaw, Kay-Tee and Forouhi, Nita G and Wareham, Nicholas J and Langenberg, Claudia} } @article {1164, title = {Dynamic cardiovascular risk assessment in elderly people. The role of repeated N-terminal pro-B-type natriuretic peptide testing.}, journal = {J Am Coll Cardiol}, volume = {55}, year = {2010}, month = {2010 Feb 02}, pages = {441-50}, abstract = {

OBJECTIVES: This study sought to determine whether serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in community-dwelling elderly people would provide additional prognostic information to that from traditional risk factors.

BACKGROUND: Accurate cardiovascular risk stratification is challenging in elderly people.

METHODS: NT-proBNP was measured at baseline and 2 to 3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal CHS (Cardiovascular Health Study). This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders.

RESULTS: NT-proBNP levels in the highest quintile (>267.7 pg/ml) were independently associated with greater risks of HF (hazard ratio [HR]: 3.05; 95\% confidence interval [CI]: 2.46 to 3.78) and cardiovascular death (HR: 3.02; 95\% CI: 2.36 to 3.86) compared with the lowest quintile (<47.5 pg/ml). The inflection point for elevated risk occurred at NT-proBNP 190 pg/ml. Among participants with initially low NT-proBNP (<190 pg/ml), those who developed a >25\% increase on follow-up to >190 pg/ml (21\%) were at greater adjusted risk of HF (HR: 2.13; 95\% CI: 1.68 to 2.71) and cardiovascular death (HR: 1.91; 95\% CI: 1.43 to 2.53) compared with those with sustained low levels. Among participants with initially high NT-proBNP, those who developed a >25\% increase (40\%) were at higher risk of HF (HR: 2.06; 95\% CI: 1.56 to 2.72) and cardiovascular death (HR: 1.88; 95\% CI: 1.37 to 2.57), whereas those who developed a >25\% decrease to

CONCLUSIONS: NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time, and these fluctuations reflect dynamic changes in cardiovascular risk.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2009.07.069}, author = {deFilippi, Christopher R and Christenson, Robert H and Gottdiener, John S and Kop, Willem J and Seliger, Stephen L} } @article {1270, title = {Depressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study.}, journal = {Heart}, volume = {97}, year = {2011}, month = {2011 Mar}, pages = {500-5}, abstract = {

BACKGROUND: Depressed older individuals have a higher mortality than older persons without depression. Depression is associated with physical inactivity, and low levels of physical activity have been shown in some cohorts to be a partial mediator of the relationship between depression and cardiovascular events and mortality.

METHODS: A cohort of 5888 individuals (mean 72.8 {\textpm} 5.6 years, 58\% female, 16\% African-American) from four US communities was followed for an average of 10.3 years. Self-reported depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) were assessed annually and self-reported physical activity was assessed at baseline and at 3 and 7 years. To estimate how much of the increased risk of cardiovascular mortality associated with depressive symptoms was due to physical inactivity, Cox regression with time-varying covariates was used to determine the percentage change in the log HR of depressive symptoms for cardiovascular mortality after adding physical activity variables.

RESULTS: At baseline, 20\% of participants scored above the cut-off for depressive symptoms. There were 2915 deaths (49.8\%), of which 1176 (20.1\%) were from cardiovascular causes. Depressive symptoms and physical inactivity each independently increased the risk of cardiovascular mortality and were strongly associated with each other (all p < 0.001). Individuals with both depressive symptoms and physical inactivity had greater cardiovascular mortality than those with either individually (p < 0.001, log rank test). Physical inactivity reduced the log HR of depressive symptoms for cardiovascular mortality by 26\% after adjustment. This was similar for persons with (25\%) and without (23\%) established coronary heart disease.

CONCLUSIONS: Physical inactivity accounted for a significant proportion of the risk of cardiovascular mortality due to depressive symptoms in older adults, regardless of coronary heart disease status.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Depression, Epidemiologic Methods, Female, Humans, Male, Motor Activity, Psychiatric Status Rating Scales, United States}, issn = {1468-201X}, doi = {10.1136/hrt.2010.209767}, author = {Win, Sithu and Parakh, Kapil and Eze-Nliam, Chete M and Gottdiener, John S and Kop, Willem J and Ziegelstein, Roy C} } @article {1272, title = {Diabetes mellitus, fasting glucose, and risk of cause-specific death.}, journal = {N Engl J Med}, volume = {364}, year = {2011}, month = {2011 Mar 03}, pages = {829-841}, abstract = {

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95\% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95\% CI, 1.19 to 1.31) for death from cancer, 2.32 (95\% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95\% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40\% of the difference in survival attributable to excess nonvascular deaths.

CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

}, keywords = {Blood Glucose, Cause of Death, Diabetes Mellitus, Female, Humans, Hyperglycemia, Life Expectancy, Male, Middle Aged, Risk, Survival Analysis}, issn = {1533-4406}, doi = {10.1056/NEJMoa1008862}, author = {Rao Kondapally Seshasai, Sreenivasa and Kaptoge, Stephen and Thompson, Alexander and Di Angelantonio, Emanuele and Gao, Pei and Sarwar, Nadeem and Whincup, Peter H and Mukamal, Kenneth J and Gillum, Richard F and Holme, Ingar and Nj{\o}lstad, Inger and Fletcher, Astrid and Nilsson, Peter and Lewington, Sarah and Collins, Rory and Gudnason, Vilmundur and Thompson, Simon G and Sattar, Naveed and Selvin, Elizabeth and Hu, Frank B and Danesh, John} } @article {1241, title = {Diastolic blood pressure levels and ischemic stroke incidence in older adults with white matter lesions.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Jan}, pages = {74-81}, abstract = {

BACKGROUND: The optimal blood pressure level to minimize the risk of ischemic stroke (IS) in older adults is undetermined. Cerebral white matter lesions (WML), prevalent in older adults, may be a marker for vulnerability to IS. We aimed at determining the relationship between diastolic blood pressure (DBP) levels and IS in the presence of WML.

METHODS: The Cardiovascular Health Study population (N = 3,345, age >= 65 years, N = 3,345) was followed between 1989 and 2002 for IS incidence. Survival analysis included quintiles of DBP analyzed within WML levels controlling for age and cardiovascular disease.

RESULTS: DBP had no effect on IS incidence in low WML levels but had a marginally significant J-curve relationship with IS in high WML levels: the adjusted hazard ratio for IS in the lowest (<63 mmHg) and highest (>= 80) DBP quintiles compared with the third (nadir, 69-73 mmHg) was 1.64 (95\% confidence interval: 0.93-2.9) and 1.83 (95\% confidence interval: 1.06-3.15), respectively.

CONCLUSIONS: In older adults with low-grade WML, low DBP may not pose a risk for IS. However, in high-grade WML, IS risk may increase in DBP less than 69 mmHg but is highest more than 80 mmHg. People with high-grade WML may be at risk of IS in high and low DBP.

}, keywords = {Aged, Aged, 80 and over, Brain, Brain Ischemia, Cerebrovascular Circulation, Diastole, Female, Humans, Incidence, Male, Multivariate Analysis, Stroke}, issn = {1758-535X}, doi = {10.1093/gerona/glq166}, author = {Reshef, Shoshana and Fried, Linda and Beauchamp, Norman and Scharfstein, Daniel and Reshef, Daniel and Goodman, Steven} } @article {1374, title = {Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {1970-6}, abstract = {

BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.

STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.

RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10\% decreases over time in IGF-I levels (CM = 29.6\%), individuals who had at least 10\% increases over time in IGF-I levels (CM = 24.7\%), and individuals who had IGF-I levels remaining within {\textpm}10\% over time (CM = 23.5\%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38\% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95\% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95\% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.

CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Longitudinal Studies, Male, Mortality, Predictive Value of Tests, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2011-2967}, author = {Kaplan, Robert C and B{\r u}zkov{\'a}, Petra and Cappola, Anne R and Strickler, Howard D and McGinn, Aileen P and Mercer, Laina D and Arnold, Alice M and Pollak, Michael N and Newman, Anne B} } @article {1408, title = {Development and validation of a coronary risk prediction model for older U.S. and European persons in the Cardiovascular Health Study and the Rotterdam Study.}, journal = {Ann Intern Med}, volume = {157}, year = {2012}, month = {2012 Sep 18}, pages = {389-97}, abstract = {

BACKGROUND: Risk scores for prediction of coronary heart disease (CHD) in older adults are needed.

OBJECTIVE: To develop a sex-specific CHD risk prediction model for older adults that accounts for competing risks for death.

DESIGN: 2 observational cohort studies, using data from 4946 participants in the Cardiovascular Health Study (CHS) and 4303 participants in the Rotterdam Study (RS).

SETTING: Community settings in the United States (CHS) and Rotterdam, the Netherlands (RS).

PARTICIPANTS: Persons aged 65 years or older who were free of cardiovascular disease.

MEASUREMENTS: A composite of nonfatal myocardial infarction and coronary death.

RESULTS: During a median follow-up of 16.5 and 14.9 years, 1166 CHS and 698 RS participants had CHD events, respectively. Deaths from noncoronary causes largely exceeded the number of CHD events, complicating accurate CHD risk predictions. The prediction model had moderate ability to discriminate between events and nonevents (c-statistic, 0.63 in both U.S. and European men and 0.67 and 0.68 in U.S. and European women). The model was well-calibrated; predicted risks were in good agreement with observed risks. Compared with the Framingham point scores, the prediction model classified elderly U.S. persons into higher risk categories but elderly European persons into lower risk categories. Differences in classification accuracy were not consistent and depended on cohort and sex. Adding newer cardiovascular risk markers to the model did not substantially improve performance.

LIMITATION: The model may be less applicable in nonwhite populations, and the comparison Framingham model was not designed for adults older than 79 years.

CONCLUSION: A CHD risk prediction model that accounts for deaths from noncoronary causes among older adults provided well-calibrated risk estimates but was not substantially more accurate than Framingham point scores. Moreover, adding newer risk markers did not improve accuracy. These findings emphasize the difficulties of predicting CHD risk in elderly persons and the need to improve these predictions.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; The Netherlands Organisation for Scientific Research; and the Netherlands Organisation for Health Research and Development.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Cause of Death, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Male, Models, Statistical, Multivariate Analysis, Netherlands, Prospective Studies, Risk Assessment, Risk Factors, United States}, issn = {1539-3704}, doi = {10.7326/0003-4819-157-6-201209180-00002}, author = {Koller, Michael T and Leening, Maarten J G and Wolbers, Marcel and Steyerberg, Ewout W and Hunink, M G Myriam and Schoop, Rotraut and Hofman, Albert and Bucher, Heiner C and Psaty, Bruce M and Lloyd-Jones, Donald M and Witteman, Jacqueline C M} } @article {5992, title = {Decline in health for older adults: five-year change in 13 key measures of standardized health.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {68}, year = {2013}, month = {2013 Sep}, pages = {1059-67}, abstract = {

BACKGROUND: The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others.

METHODS: We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest.

RESULTS: The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization.

CONCLUSIONS: All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions.

}, keywords = {Activities of Daily Living, Aged, Aging, Cohort Studies, Female, Gait, Health Status, Health Status Indicators, Hospitalization, Humans, Longitudinal Studies, Male, Mental Health, Quality of Life, Self Report, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt038}, author = {Diehr, Paula H and Thielke, Stephen M and Newman, Anne B and Hirsch, Calvin and Tracy, Russell} } @article {6154, title = {Discovery and refinement of loci associated with lipid levels.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Nov}, pages = {1274-1283}, abstract = {

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 {\texttimes} 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

}, keywords = {African Continental Ancestry Group, Asian Continental Ancestry Group, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lipids, Triglycerides}, issn = {1546-1718}, doi = {10.1038/ng.2797}, author = {Willer, Cristen J and Schmidt, Ellen M and Sengupta, Sebanti and Peloso, Gina M and Gustafsson, Stefan and Kanoni, Stavroula and Ganna, Andrea and Chen, Jin and Buchkovich, Martin L and Mora, Samia and Beckmann, Jacques S and Bragg-Gresham, Jennifer L and Chang, Hsing-Yi and Demirkan, Ayse and Den Hertog, Heleen M and Do, Ron and Donnelly, Louise A and Ehret, Georg B and Esko, T{\~o}nu and Feitosa, Mary F and Ferreira, Teresa and Fischer, Krista and Fontanillas, Pierre and Fraser, Ross M and Freitag, Daniel F and Gurdasani, Deepti and Heikkil{\"a}, Kauko and Hypp{\"o}nen, Elina and Isaacs, Aaron and Jackson, Anne U and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kettunen, Johannes and Kleber, Marcus E and Li, Xiaohui and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Mangino, Massimo and Mihailov, Evelin and Montasser, May E and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and O{\textquoteright}Connell, Jeffrey R and Palmer, Cameron D and Perola, Markus and Petersen, Ann-Kristin and Sanna, Serena and Saxena, Richa and Service, Susan K and Shah, Sonia and Shungin, Dmitry and Sidore, Carlo and Song, Ci and Strawbridge, Rona J and Surakka, Ida and Tanaka, Toshiko and Teslovich, Tanya M and Thorleifsson, Gudmar and van den Herik, Evita G and Voight, Benjamin F and Volcik, Kelly A and Waite, Lindsay L and Wong, Andrew and Wu, Ying and Zhang, Weihua and Absher, Devin and Asiki, Gershim and Barroso, In{\^e}s and Been, Latonya F and Bolton, Jennifer L and Bonnycastle, Lori L and Brambilla, Paolo and Burnett, Mary S and Cesana, Giancarlo and Dimitriou, Maria and Doney, Alex S F and D{\"o}ring, Angela and Elliott, Paul and Epstein, Stephen E and Ingi Eyjolfsson, Gudmundur and Gigante, Bruna and Goodarzi, Mark O and Grallert, Harald and Gravito, Martha L and Groves, Christopher J and Hallmans, G{\"o}ran and Hartikainen, Anna-Liisa and Hayward, Caroline and Hernandez, Dena and Hicks, Andrew A and Holm, Hilma and Hung, Yi-Jen and Illig, Thomas and Jones, Michelle R and Kaleebu, Pontiano and Kastelein, John J P and Khaw, Kay-Tee and Kim, Eric and Klopp, Norman and Komulainen, Pirjo and Kumari, Meena and Langenberg, Claudia and Lehtim{\"a}ki, Terho and Lin, Shih-Yi and Lindstr{\"o}m, Jaana and Loos, Ruth J F and Mach, Fran{\c c}ois and McArdle, Wendy L and Meisinger, Christa and Mitchell, Braxton D and M{\"u}ller, Gabrielle and Nagaraja, Ramaiah and Narisu, Narisu and Nieminen, Tuomo V M and Nsubuga, Rebecca N and Olafsson, Isleifur and Ong, Ken K and Palotie, Aarno and Papamarkou, Theodore and Pomilla, Cristina and Pouta, Anneli and Rader, Daniel J and Reilly, Muredach P and Ridker, Paul M and Rivadeneira, Fernando and Rudan, Igor and Ruokonen, Aimo and Samani, Nilesh and Scharnagl, Hubert and Seeley, Janet and Silander, Kaisa and Stan{\v c}{\'a}kov{\'a}, Alena and Stirrups, Kathleen and Swift, Amy J and Tiret, Laurence and Uitterlinden, Andr{\'e} G and van Pelt, L Joost and Vedantam, Sailaja and Wainwright, Nicholas and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilsgaard, Tom and Wilson, James F and Young, Elizabeth H and Zhao, Jing Hua and Adair, Linda S and Arveiler, Dominique and Assimes, Themistocles L and Bandinelli, Stefania and Bennett, Franklyn and Bochud, Murielle and Boehm, Bernhard O and Boomsma, Dorret I and Borecki, Ingrid B and Bornstein, Stefan R and Bovet, Pascal and Burnier, Michel and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chen, Yii-Der Ida and Collins, Francis S and Cooper, Richard S and Danesh, John and Dedoussis, George and de Faire, Ulf and Feranil, Alan B and Ferrieres, Jean and Ferrucci, Luigi and Freimer, Nelson B and Gieger, Christian and Groop, Leif C and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hingorani, Aroon and Hirschhorn, Joel N and Hofman, Albert and Hovingh, G Kees and Hsiung, Chao Agnes and Humphries, Steve E and Hunt, Steven C and Hveem, Kristian and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kes{\"a}niemi, Antero and Kivimaki, Mika and Kooner, Jaspal S and Koudstaal, Peter J and Krauss, Ronald M and Kuh, Diana and Kuusisto, Johanna and Kyvik, Kirsten O and Laakso, Markku and Lakka, Timo A and Lind, Lars and Lindgren, Cecilia M and Martin, Nicholas G and M{\"a}rz, Winfried and McCarthy, Mark I and McKenzie, Colin A and Meneton, Pierre and Metspalu, Andres and Moilanen, Leena and Morris, Andrew D and Munroe, Patricia B and Nj{\o}lstad, Inger and Pedersen, Nancy L and Power, Chris and Pramstaller, Peter P and Price, Jackie F and Psaty, Bruce M and Quertermous, Thomas and Rauramaa, Rainer and Saleheen, Danish and Salomaa, Veikko and Sanghera, Dharambir K and Saramies, Jouko and Schwarz, Peter E H and Sheu, Wayne H-H and Shuldiner, Alan R and Siegbahn, Agneta and Spector, Tim D and Stefansson, Kari and Strachan, David P and Tayo, Bamidele O and Tremoli, Elena and Tuomilehto, Jaakko and Uusitupa, Matti and van Duijn, Cornelia M and Vollenweider, Peter and Wallentin, Lars and Wareham, Nicholas J and Whitfield, John B and Wolffenbuttel, Bruce H R and Ordovas, Jose M and Boerwinkle, Eric and Palmer, Colin N A and Thorsteinsdottir, Unnur and Chasman, Daniel I and Rotter, Jerome I and Franks, Paul W and Ripatti, Samuli and Cupples, L Adrienne and Sandhu, Manjinder S and Rich, Stephen S and Boehnke, Michael and Deloukas, Panos and Kathiresan, Sekar and Mohlke, Karen L and Ingelsson, Erik and Abecasis, Goncalo R} } @article {6554, title = {Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.}, journal = {JAMA}, volume = {311}, year = {2014}, month = {2014 Jun 25}, pages = {2518-2531}, abstract = {

IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of -57\% or greater) is a late event.

OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.

DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.

DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.

MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.

RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95\% CI, 22.3-46.3) for changes of -57\% in estimated GFR and 5.4 (95\% CI, 4.5-6.4) for changes of -30\%. However, changes of -30\% or greater (6.9\% [95\% CI, 6.4\%-7.4\%] of the entire consortium) were more common than changes of -57\% (0.79\% [95\% CI, 0.52\%-1.06\%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99\% (95\% CI, 95\%-100\%) for estimated GFR change of -57\%, was 83\% (95\% CI, 71\%-93\%) for estimated GFR change of -40\%, and was 64\% (95\% CI, 52\%-77\%) for estimated GFR change of -30\% vs 18\% (95\% CI, 15\%-22\%) for estimated GFR change of 0\%. Corresponding mortality risks were 77\% (95\% CI, 71\%-82\%), 60\% (95\% CI, 56\%-63\%), and 50\% (95\% CI, 47\%-52\%) vs 32\% (95\% CI, 31\%-33\%), showing a similar but weaker pattern.

CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30\% reduction over 2 years) as an alternative end point for CKD progression.

}, keywords = {Adult, Aged, Aged, 80 and over, Cohort Studies, Creatinine, Disease Progression, Endpoint Determination, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Reference Values, Risk}, issn = {1538-3598}, doi = {10.1001/jama.2014.6634}, author = {Coresh, Josef and Turin, Tanvir Chowdhury and Matsushita, Kunihiro and Sang, Yingying and Ballew, Shoshana H and Appel, Lawrence J and Arima, Hisatomi and Chadban, Steven J and Cirillo, Massimo and Djurdjev, Ognjenka and Green, Jamie A and Heine, Gunnar H and Inker, Lesley A and Irie, Fujiko and Ishani, Areef and Ix, Joachim H and Kovesdy, Csaba P and Marks, Angharad and Ohkubo, Takayoshi and Shalev, Varda and Shankar, Anoop and Wen, Chi Pang and de Jong, Paul E and Iseki, Kunitoshi and Stengel, B{\'e}n{\'e}dicte and Gansevoort, Ron T and Levey, Andrew S} } @article {6302, title = {Development and validation of a brief dementia screening indicator for primary care.}, journal = {Alzheimers Dement}, volume = {10}, year = {2014}, month = {2014 Nov}, pages = {656-665.e1}, abstract = {

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.

METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.

RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12~years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5~kg/m(2) (8 points), requiring assistance with money or medications (10 points), and~depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell{\textquoteright}s C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).

CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

}, keywords = {Aged, Cohort Studies, Dementia, Female, Humans, Male, Mass Screening, Predictive Value of Tests, Primary Health Care, Proportional Hazards Models, Risk Assessment}, issn = {1552-5279}, doi = {10.1016/j.jalz.2013.11.006}, author = {Barnes, Deborah E and Beiser, Alexa S and Lee, Anne and Langa, Kenneth M and Koyama, Alain and Preis, Sarah R and Neuhaus, John and McCammon, Ryan J and Yaffe, Kristine and Seshadri, Sudha and Haan, Mary N and Weir, David R} } @article {6803, title = {Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.}, journal = {Eur J Prev Cardiol}, volume = {21}, year = {2014}, month = {2014 Mar}, pages = {310-20}, abstract = {

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.

DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.

METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.

RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95\% CI 0.599 to 0.737) in men and 0.578 (95\% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95\% CI 0.612 to 0.749) and large increase in women to 0.690 (95\% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3\% (95\% CI 0.0 to 7.6\%, p = 0.050) and 9.6\% (95\% CI 6.1 to 16.4\%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19\% resulted in higher NRI of 15.9\% (95\% CI 6.1 to 20.6\%, p < 0.001) in men and 23.3\% (95\% CI 13.8 to 62.5\%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0\% (95\% CI 2.3 to 4.2\%, p = 0.567) in men and 1.1\% (95\% CI 1.9 to 4.0\%, p = 0.483) in women.

CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

}, keywords = {Adult, Aged, Aged, 80 and over, Ankle Brachial Index, Cardiovascular Diseases, Europe, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Prognosis, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Time Factors, United States, Young Adult}, issn = {2047-4881}, doi = {10.1177/2047487313516564}, author = {Fowkes, F G R and Murray, G D and Butcher, I and Folsom, A R and Hirsch, A T and Couper, D J and deBacker, G and Kornitzer, M and Newman, A B and Sutton-Tyrrell, K C and Cushman, M and Lee, A J and Price, J F and D{\textquoteright}Agostino, R B and Murabito, J M and Norman, Pe and Masaki, K H and Bouter, L M and Heine, R J and Stehouwer, C D A and McDermott, M M and Stoffers, H E J H and Knottnerus, J A and Ogren, M and Hedblad, B and Koenig, W and Meisinger, C and Cauley, J A and Franco, Oh and Hunink, M G M and Hofman, A and Witteman, J C and Criqui, M H and Langer, R D and Hiatt, W R and Hamman, R F} } @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 {6560, title = {Disability and recovery of independent function in obstructive lung disease: the cardiovascular health study.}, journal = {Respiration}, volume = {88}, year = {2014}, month = {2014}, pages = {329-38}, abstract = {

BACKGROUND: Chronic obstructive lung disease frequently leads to disability. Older patients may experience transitions between states of disability and independence over time.

OBJECTIVE: To identify factors associated with transition between states of disability and independent function in obstructive lung disease.

METHODS: We analyzed data on 4,394 participants in the Cardiovascular Health Study who completed prebronchodilator spirometry. We calculated the 1-year probability of developing and resolving impairment in >=1 instrumental activity of daily living (IADL) or >=1 activity of daily living (ADL) using transition probability analysis. We identified factors associated with resolving disability using relative risk (RR) regression.

RESULTS: The prevalence of IADL impairment was higher with moderate (23.9\%) and severe (36.9\%) airflow obstruction compared to normal spirometry (22.5\%; p < 0.001). Among participants with severe airflow obstruction, 23.5\% recovered independence in IADLs and 40.5\% recovered independence in ADLs. In the adjusted analyses, airflow obstruction predicted the development of IADL, but not ADL impairment. Participants with severe airflow obstruction were less likely to resolve IADL impairment [RR 0.67 and 95\% confidence interval (CI) 0.49-0.94]. Compared to the most active individuals (i.e. who walked >=28 blocks per week), walking less was associated with a decreased likelihood of resolving IADL impairment (7-27 blocks: RR 0.81 and 95\% CI 0.69-0.86 and <7 blocks: RR 0.73 and 95\% CI 0.61-0.86). Increased strength (RR 1.16 and 95\% CI 1.05-1.29) was associated with resolving IADL impairment.

CONCLUSIONS: Disability is common in older people, especially in those with severe airflow obstruction. Increased physical activity and muscle strength are associated with recovery. Research is needed on interventions to improve these factors among patients with obstructive lung disease and disability.

}, keywords = {Activities of Daily Living, Aged, Cardiac Rehabilitation, Cardiovascular Diseases, Disability Evaluation, Exercise Test, Female, Humans, Independent Living, Longitudinal Studies, Male, Motor Activity, Muscle Strength, Outcome Assessment (Health Care), Pulmonary Disease, Chronic Obstructive, Recovery of Function, Risk Assessment, Severity of Illness Index, Spirometry, United States}, issn = {1423-0356}, doi = {10.1159/000363772}, author = {Fan, Vincent S and Locke, Emily R and Diehr, Paula and Wilsdon, Anthony and Enright, Paul and Yende, Sachin and Avdalovic, Mark and Barr, Graham and Kapur, Vishesh K and Thomas, Rachel and Krishnan, Jerry A and Lovasi, Gina and Thielke, Stephen} } @article {6000, title = {Do changes in circulating biomarkers track with each other and with functional changes in older adults?}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {174-81}, abstract = {

BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.

METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.

RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).

CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Aging, Biomarkers, Cholesterol, Cognition, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Gait, Hand Strength, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Interleukin-6, Male, Neuropsychological Tests, Psychomotor Performance, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt088}, author = {Sanders, Jason L and Ding, Victoria and Arnold, Alice M and Kaplan, Robert C and Cappola, Anne R and Kizer, Jorge R and Boudreau, Robert M and Cushman, Mary and Newman, Anne B} } @article {5978, title = {Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.}, journal = {Pharmacogenomics J}, volume = {14}, year = {2014}, month = {2014 Feb}, pages = {6-13}, abstract = {

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the {\textquoteright}missing heritability{\textquoteright} of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0\%), tri/tetracyclic antidepressants (2.6\%), sulfonylurea hypoglycemic agents (2.9\%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4\%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 {\texttimes} 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

}, keywords = {Computer Simulation, Cross-Sectional Studies, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, European Continental Ancestry Group, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Linear Models, Long QT Syndrome, Markov Chains, Pharmacogenetics, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable}, issn = {1473-1150}, doi = {10.1038/tpj.2013.4}, author = {Avery, C L and Sitlani, C M and Arking, D E and Arnett, D K and Bis, J C and Boerwinkle, E and Buckley, B M and Ida Chen, Y-D and de Craen, A J M and Eijgelsheim, M and Enquobahrie, D and Evans, D S and Ford, I and Garcia, M E and Gudnason, V and Harris, T B and Heckbert, S R and Hochner, H and Hofman, A and Hsueh, W-C and Isaacs, A and Jukema, J W and Knekt, P and Kors, J A and Krijthe, B P and Kristiansson, K and Laaksonen, M and Liu, Y and Li, X and Macfarlane, P W and Newton-Cheh, C and Nieminen, M S and Oostra, B A and Peloso, G M and Porthan, K and Rice, K and Rivadeneira, F F and Rotter, J I and Salomaa, V and Sattar, N and Siscovick, D S and Slagboom, P E and Smith, A V and Sotoodehnia, N and Stott, D J and Stricker, B H and St{\"u}rmer, T and Trompet, S and Uitterlinden, A G and van Duijn, C and Westendorp, R G J and Witteman, J C and Whitsel, E A and Psaty, B M} } @article {6817, title = {DCAF4, a novel gene associated with leucocyte telomere length.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Mar}, pages = {157-62}, abstract = {

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4{\texttimes}10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1{\texttimes}10(-3) and 2{\texttimes}10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97{\texttimes}10(-169) to 3.42{\texttimes}10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

}, keywords = {Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2014-102681}, author = {Mangino, Massimo and Christiansen, Lene and Stone, Rivka and Hunt, Steven C and Horvath, Kent and Eisenberg, Dan T A and Kimura, Masayuki and Petersen, Inge and Kark, Jeremy D and Herbig, Utz and Reiner, Alex P and Benetos, Athanase and Codd, Veryan and Nyholt, Dale R and Sinnreich, Ronit and Christensen, Kaare and Nassar, Hisham and Hwang, Shih-Jen and Levy, Daniel and Bataille, Veronique and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Samani, Nilesh J and Martin, Nicholas G and Tishkoff, Sarah and Schork, Nicholas J and Kyvik, Kirsten Ohm and Dalg{\r a}rd, Christine and Spector, Timothy D and Aviv, Abraham} } @article {6659, title = {Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Mar 6}, pages = {363-71}, abstract = {

BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.

RESULTS: The development cohort included 828 participants who had a mean age of 80 ({\textpm}5.6) years and an eGFR of 47 ({\textpm}11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 ({\textpm}2.8) years and an eGFR of 50 ({\textpm}9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95\% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8\% among participants with the lowest scores to 83.6\% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95\% confidence interval, 0.64 to 0.74).

CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Continental Population Groups, Creatinine, Diabetes Mellitus, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Regression Analysis, Renal Insufficiency, Chronic, Risk Factors, Sex Factors, Smoking, Stroke}, issn = {1555-905X}, doi = {10.2215/CJN.04650514}, author = {Bansal, Nisha and Katz, Ronit and de Boer, Ian H and Peralta, Carmen A and Fried, Linda F and Siscovick, David S and Rifkin, Dena E and Hirsch, Calvin and Cummings, Steven R and Harris, Tamara B and Kritchevsky, Stephen B and Sarnak, Mark J and Shlipak, Michael G and Ix, Joachim H} } @article {6687, title = {Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.}, journal = {Mol Nutr Food Res}, volume = {59}, year = {2015}, month = {2015 Jul}, pages = {1373-83}, abstract = {

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

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

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

}, keywords = {Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1613-4133}, doi = {10.1002/mnfr.201400734}, author = {Smith, Caren E and Follis, Jack L and Nettleton, Jennifer A and Foy, Millennia and Wu, Jason H Y and Ma, Yiyi and Tanaka, Toshiko and Manichakul, Ani W and Wu, Hongyu and Chu, Audrey Y and Steffen, Lyn M and Fornage, Myriam and Mozaffarian, Dariush and Kabagambe, Edmond K and Ferruci, Luigi and Chen, Yii-Der Ida and Rich, Stephen S and Djouss{\'e}, Luc and Ridker, Paul M and Tang, Weihong and McKnight, Barbara and Tsai, Michael Y and Bandinelli, Stefania and Rotter, Jerome I and Hu, Frank B and Chasman, Daniel I and Psaty, Bruce M and Arnett, Donna K and King, Irena B and Sun, Qi and Wang, Lu and Lumley, Thomas and Chiuve, Stephanie E and Siscovick, David S and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0{\texttimes}10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} } @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 {6905, title = {Diabetes mellitus and venous thromboembolism: A systematic review and meta-analysis.}, journal = {Diabetes Res Clin Pract}, volume = {111}, year = {2016}, month = {2016 Jan}, pages = {10-8}, abstract = {

UNLABELLED: Diabetes mellitus (DM) may be a risk factor for venous thromboembolism (VTE) but results are inconsistent.

AIM: We conducted a systematic review and meta-analysis of epidemiologic studies to quantify the association between DM and VTE.

METHODS AND RESULTS: We included studies identified in PubMed, Web of Science, and CINAHL through 07/31/2014. We identified 19 studies that met our selection criteria. We pooled RRs using a random-effects model: the pooled RR for the association of DM with VTE was 1.10 (95\% CI: 0.94-1.29). Between-study heterogeneity was explored with a forest plot, funnel plot, meta-regression, and a stratified analysis. Between-study heterogeneity was observed and not explained by study design, method of DM assessment, or degree of adjustment for confounding. Sensitivity analyses omitted one study at a time to assess the influence of any single study on the pooled estimate. These analyses indicated that one large study was highly influential; when this study was excluded, the pooled estimate increased and just reached statistical significance: 1.16 (95\% CI: 1.01-1.34).

CONCLUSIONS: This meta-analysis suggests either no association or a modest positive one between DM and VTE in the general population. DM is unlikely to play a major role in VTE development.

}, issn = {1872-8227}, doi = {10.1016/j.diabres.2015.10.019}, author = {Bell, Elizabeth J and Folsom, Aaron R and Lutsey, Pamela L and Selvin, Elizabeth and Zakai, Neil A and Cushman, Mary and Alonso, Alvaro} } @article {7010, title = {Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.}, journal = {J Am Coll Cardiol}, volume = {67}, year = {2016}, month = {2016 Jun 7}, pages = {2578-89}, abstract = {

BACKGROUND: Approximately 7\% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol~>=190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by~a~single LDL cholesterol measurement.

OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.

METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.

RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7\%) had LDL cholesterol >=190~mg/dl; of these, only 24 (1.7\%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol~>=190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95\% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol~>=190 mg/dl and~an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95\% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.

CONCLUSIONS: Among participants with LDL cholesterol~>=190 mg/dl, gene sequencing identified an FH mutation in~<2\%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.03.520}, author = {Khera, Amit V and Won, Hong-Hee and Peloso, Gina M and Lawson, Kim S and Bartz, Traci M and Deng, Xuan and van Leeuwen, Elisabeth M and Natarajan, Pradeep and Emdin, Connor A and Bick, Alexander G and Morrison, Alanna C and Brody, Jennifer A and Gupta, Namrata and Nomura, Akihiro and Kessler, Thorsten and Duga, Stefano and Bis, Joshua C and van Duijn, Cornelia M and Cupples, L Adrienne and Psaty, Bruce and Rader, Daniel J and Danesh, John and Schunkert, Heribert and McPherson, Ruth and Farrall, Martin and Watkins, Hugh and Lander, Eric and Wilson, James G and Correa, Adolfo and Boerwinkle, Eric and Merlini, Piera Angelica and Ardissino, Diego and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} } @article {7131, title = {Digit Symbol Substitution test and future clinical and subclinical disorders of cognition, mobility and mood in older adults.}, journal = {Age Ageing}, volume = {45}, year = {2016}, month = {2016 Sep}, pages = {688-95}, abstract = {

OBJECTIVE: to examine whether psychomotor speed predicts individual and combined disorders in cognition, mobility and mood and if white matter hyperintensities explain these associations.

DESIGN AND SETTING: longitudinal; Cardiovascular Health Study.

SUBJECTS: 5,888 participants (57.6\% women, 15.7\% black, 75.1 (5.5), mean years (SD)).

METHODS: psychomotor speed (Digit Symbol Substitution Test (DSST)) and small vessel disease (white matter hyperintensities (WMH)) were measured in 1992-94. Global cognition (Modified Mini-Mental State (3MS) examination), mobility (gait speed (GS)) and mood (Center for Epidemiologic Studies Depression (CES-D) scale) were measured annually over 5 years and classified as clinical, subclinical or no disorders based on established values (3MS: 80 and 85 points; GS: 0.6 and 1.0 m/s; CES-D: 10 and 5 points). Analyses were adjusted for demographics, baseline status, education, diabetes, hypertension, ankle-arm index.

RESULTS: among those with no disorder in cognition, mobility and mood (N~=~619) in 1992-94, being in the lowest DSST quartile compared to the highest was associated with nearly twice the odds of developing 1+ clinical or subclinical disorders (N~=~413) during follow-up. Associations were stronger for incident clinical disorders in cognition (OR: 8.44, p~<~0.01) or mobility (OR: 9.09, p~<~0.05) than for mood (OR: 1.88, p~<~0.10). Results were similar after adjustment for WMH.

CONCLUSIONS: slower psychomotor speed may serve as a biomarker of risk of clinical disorders of cognition, mobility and mood. While in part attributable to vascular brain disease, other potentially modifiable contributors may be present. Further studying the causes of psychomotor slowing with ageing might provide novel insights into age-related brain disorders.

}, issn = {1468-2834}, doi = {10.1093/ageing/afw116}, author = {Rosano, Caterina and Perera, Subashan and Inzitari, Marco and Newman, Anne B and Longstreth, William T and Studenski, Stephanie} } @article {7144, title = {Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 May}, pages = {e1006034}, abstract = {

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36\% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006034}, author = {Smith, J Gustav and Felix, Janine F and Morrison, Alanna C and Kalogeropoulos, Andreas and Trompet, Stella and Wilk, Jemma B and Gidl{\"o}f, Olof and Wang, Xinchen and Morley, Michael and Mendelson, Michael and Joehanes, Roby and Ligthart, Symen and Shan, Xiaoyin and Bis, Joshua C and Wang, Ying A and Sj{\"o}gren, Marketa and Ngwa, Julius and Brandimarto, Jeffrey and Stott, David J and Aguilar, David and Rice, Kenneth M and Sesso, Howard D and Demissie, Serkalem and Buckley, Brendan M and Taylor, Kent D and Ford, Ian and Yao, Chen and Liu, Chunyu and Sotoodehnia, Nona and van der Harst, Pim and Stricker, Bruno H Ch and Kritchevsky, Stephen B and Liu, Yongmei and Gaziano, J Michael and Hofman, Albert and Moravec, Christine S and Uitterlinden, Andr{\'e} G and Kellis, Manolis and van Meurs, Joyce B and Margulies, Kenneth B and Dehghan, Abbas and Levy, Daniel and Olde, Bj{\"o}rn and Psaty, Bruce M and Cupples, L Adrienne and Jukema, J Wouter and Djouss{\'e}, Luc and Franco, Oscar H and Boerwinkle, Eric and Boyer, Laurie A and Newton-Cheh, Christopher and Butler, Javed and Vasan, Ramachandran S and Cappola, Thomas P and Smith, Nicholas L} } @article {7375, title = {A DNA methylation biomarker of alcohol consumption.}, journal = {Mol Psychiatry}, year = {2016}, month = {2016 Nov 15}, abstract = {

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54\% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 {\texttimes} 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 {\texttimes} 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Molecular Psychiatry advance online publication, 15 November 2016; doi:10.1038/mp.2016.192.

}, issn = {1476-5578}, doi = {10.1038/mp.2016.192}, author = {Liu, C and Marioni, R E and Hedman, {\r A} K and Pfeiffer, L and Tsai, P-C and Reynolds, L M and Just, A C and Duan, Q and Boer, C G and Tanaka, T and Elks, C E and Aslibekyan, S and Brody, J A and K{\"u}hnel, B and Herder, C and Almli, L M and Zhi, D and Wang, Y and Huan, T and Yao, C and Mendelson, M M and Joehanes, R and Liang, L and Love, S-A and Guan, W and Shah, S and McRae, A F and Kretschmer, A and Prokisch, H and Strauch, K and Peters, A and Visscher, P M and Wray, N R and Guo, X and Wiggins, K L and Smith, A K and Binder, E B and Ressler, K J and Irvin, M R and Absher, D M and Hernandez, D and Ferrucci, L and Bandinelli, S and Lohman, K and Ding, J and Trevisi, L and Gustafsson, S and Sandling, J H and Stolk, L and Uitterlinden, A G and Yet, I and Castillo-Fernandez, J E and Spector, T D and Schwartz, J D and Vokonas, P and Lind, L and Li, Y and Fornage, M and Arnett, D K and Wareham, N J and Sotoodehnia, N and Ong, K K and van Meurs, J B J and Conneely, K N and Baccarelli, A A and Deary, I J and Bell, J T and North, K E and Liu, Y and Waldenberger, M and London, S J and Ingelsson, E and Levy, D} } @article {7349, title = {DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.}, journal = {Genome Biol}, volume = {17}, year = {2016}, month = {2016 Dec 12}, pages = {255}, abstract = {

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 {\texttimes} 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 {\texttimes} 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16\%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 {\texttimes} 10(-5)), ten (17\%) CpG sites were associated with a nearby genetic variant (P < 2.50 {\texttimes} 10(-3)), and 51 (88\%) were also associated with at least one related cardiometabolic entity (P < 9.58 {\texttimes} 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6\% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

}, issn = {1474-760X}, doi = {10.1186/s13059-016-1119-5}, author = {Ligthart, Symen and Marzi, Carola and Aslibekyan, Stella and Mendelson, Michael M and Conneely, Karen N and Tanaka, Toshiko and Colicino, Elena and Waite, Lindsay L and Joehanes, Roby and Guan, Weihua and Brody, Jennifer A and Elks, Cathy and Marioni, Riccardo and Jhun, Min A and Agha, Golareh and Bressler, Jan and Ward-Caviness, Cavin K and Chen, Brian H and Huan, Tianxiao and Bakulski, Kelly and Salfati, Elias L and Fiorito, Giovanni and Wahl, Simone and Schramm, Katharina and Sha, Jin and Hernandez, Dena G and Just, Allan C and Smith, Jennifer A and Sotoodehnia, Nona and Pilling, Luke C and Pankow, James S and Tsao, Phil S and Liu, Chunyu and Zhao, Wei and Guarrera, Simonetta and Michopoulos, Vasiliki J and Smith, Alicia K and Peters, Marjolein J and Melzer, David and Vokonas, Pantel and Fornage, Myriam and Prokisch, Holger and Bis, Joshua C and Chu, Audrey Y and Herder, Christian and Grallert, Harald and Yao, Chen and Shah, Sonia and McRae, Allan F and Lin, Honghuang and Horvath, Steve and Fallin, Daniele and Hofman, Albert and Wareham, Nicholas J and Wiggins, Kerri L and Feinberg, Andrew P and Starr, John M and Visscher, Peter M and Murabito, Joanne M and Kardia, Sharon L R and Absher, Devin M and Binder, Elisabeth B and Singleton, Andrew B and Bandinelli, Stefania and Peters, Annette and Waldenberger, Melanie and Matullo, Giuseppe and Schwartz, Joel D and Demerath, Ellen W and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B J and Franco, Oscar H and Chen, Yii-Der Ida and Levy, Daniel and Turner, Stephen T and Deary, Ian J and Ressler, Kerry J and Dupuis, Jos{\'e}e and Ferrucci, Luigi and Ong, Ken K and Assimes, Themistocles L and Boerwinkle, Eric and Koenig, Wolfgang and Arnett, Donna K and Baccarelli, Andrea A and Benjamin, Emelia J and Dehghan, Abbas} } @article {7251, title = {Dyspnea in Community-Dwelling Older Persons: A Multifactorial Geriatric Health Condition.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Oct}, pages = {2042-2050}, abstract = {

OBJECTIVES: To evaluate the associations between a broad array of cardiorespiratory and noncardiorespiratory impairments and dyspnea in older persons.

DESIGN: Cross-sectional.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Community-dwelling persons (N = 4,413; mean age 72.6, 57.1\% female, 4.5\% African American, 27.2\%

MEASUREMENTS: Dyspnea severity (moderate to severe defined as American Thoracic Society Grade >=2) and several impairments, including those established using spirometry (forced expiratory volume in 1 second (FEV1 )), maximal inspiratory pressure (respiratory muscle strength), echocardiography, ankle-brachial index, blood pressure, whole-body muscle mass (bioelectrical impedance), single chair stand (lower extremity function), grip strength, serum hemoglobin and creatinine, Center for Epidemiologic Studies Depression Scale (CES-D), Mini-Mental State Examination, medication use, and body mass index (BMI).

RESULTS: In a multivariable logistic regression model, impairments that had strong associations with moderate to severe dyspnea were FEV1 less than the lower limit of normal (adjusted odds ratio (aOR) = 2.88, 95\% confidence interval (CI) = 2.37-3.49), left ventricular ejection fraction less than 45\% (aOR = 2.12, 95\% CI = 1.43, 3.16), unable to perform a single chair stand (aOR = 2.10, 95\% CI = 1.61-2.73), depressive symptoms (CES-D score >=16; aOR = 2.02, 95\% CI = 1.26-3.23), and obesity (BMI >=30; aOR = 2.07, 95\% CI = 1.67-2.55). Impairments with modest but still statistically significant associations with moderate to severe dyspnea included respiratory muscle weakness, diastolic cardiac dysfunction, grip weakness, anxiety symptoms, and use of cardiovascular and psychoactive medications (aORs = 1.31-1.71).

CONCLUSION: In community-dwelling older persons, several cardiorespiratory and noncardiorespiratory impairments were significantly associated with moderate to severe dyspnea, akin to a multifactorial geriatric health condition.

}, issn = {1532-5415}, doi = {10.1111/jgs.14290}, author = {Miner, Brienne and Tinetti, Mary E and Van Ness, Peter H and Han, Ling and Leo-Summers, Linda and Newman, Anne B and Lee, Patty J and Vaz Fragoso, Carlos A} } @article {7452, title = {Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study.}, journal = {BMJ}, volume = {356}, year = {2017}, month = {2017 03 16}, pages = {j1000}, abstract = {

Objective~To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design~Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting~CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants~Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures~The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results~Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95\% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95\% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95\% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95\% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95\% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95\% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion~The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

}, keywords = {Blood Pressure, Dairy Products, Feeding Behavior, Genetic Predisposition to Disease, Humans, Hypertension, Lactase, Mendelian Randomization Analysis, Observational Studies as Topic, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic}, issn = {1756-1833}, doi = {10.1136/bmj.j1000}, author = {Ding, Ming and Huang, Tao and Bergholdt, Helle Km and Nordestgaard, B{\o}rge G and Ellervik, Christina and Qi, Lu} } @article {7328, title = {Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with \~{} 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (\~{}13\%) lower fetuin-A level. This variant alone explained 14\% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx091}, author = {Jensen, Majken K and Jensen, Richard A and Mukamal, Kenneth J and Guo, Xiuqing and Yao, Jie and Sun, Qi and Cornelis, Marilyn and Liu, Yongmei and Chen, Ming-Huei and Kizer, Jorge R and Djouss{\'e}, Luc and Siscovick, David S and Psaty, Bruce M and Zmuda, Joseph M and Rotter, Jerome I and Garcia, Melissa and Harris, Tamara and Chen, Ida and Goodarzi, Mark O and Nalls, Michael A and Keller, Margaux and Arnold, Alice M and Newman, Anne and Hoogeeven, Ron C and Rexrode, Kathryn M and Rimm, Eric B and Hu, Frank B and Vasan, Ramachandran S and Katz, Ronit and Pankow, James S and Ix, Joachim H} } @article {7360, title = {Development of a Claims-based Frailty Indicator Anchored to a Well-established Frailty Phenotype.}, journal = {Med Care}, year = {2017}, month = {2017 Apr 21}, abstract = {

BACKGROUND: Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (CHS). This phenotype is manifest when >=3 of the following are present: low grip strength, low energy, slowed waking speed, low physical activity, or unintentional weight loss. We sought to approximate frailty phenotype using only administrative claims data to enable frailty to be assessed without physical performance measures.

STUDY DESIGN: We used the CHS cohort data linked to participants Medicare claims. The reference standard was the frailty phenotype measured at visits 5 and 9. With penalized logistic regression, we developed a parsimonious index for predicting the frailty phenotype using a linear combination of diagnoses, operationalized with claims data. We assessed the predictive validity of frailty index by examining how well it predicted common aging-related outcomes including hospitalization, disability, and death.

RESULTS: There were 4454 CHS participants from 4 clinical sites. In total, 84\% were white, 58\% were women and their mean age was 72 years at enrollment. Approximately 11\% of the cohort was frail. The model had an area under the receiver operating curve of 0.75 to concurrently predict a frailty phenotype. This Claims-based Frailty Indicator significantly predicted death (odds ratio, 1.84), time to death (hazards ratio, 1.71), number of hospital admissions (incidence rate ratio, 1.74), and nursing home admission (odds ratio, 1.47) in models adjusted for age and sex.

CONCLUSIONS: Claims data alone can be used to classify individuals as frail and nonfrail. The Claims-based Frailty Indicator might be used in research with large datasets for confounding adjustment or risk prediction. The indicator might also be used for emergency preparedness for identification of regions enriched with frail individuals.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

}, issn = {1537-1948}, doi = {10.1097/MLR.0000000000000729}, author = {Segal, Jodi B and Chang, Hsien-Yen and Du, Yu and D Walston, Jeremy and C Carlson, Michelle and Varadhan, Ravi} } @article {7560, title = {Disability Trajectories Before and After Stroke and Myocardial Infarction: The Cardiovascular Health Study.}, journal = {JAMA Neurol}, volume = {74}, year = {2017}, month = {2017 Dec 01}, pages = {1439-1445}, abstract = {

Importance: Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function.

Objective: To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI).

Design, Settings, and Participants: In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy.

Exposures: Ischemic stroke and MI.

Main Outcomes and Measures: Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously.

Results: The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4\%) were male. During follow-up, 382 (6.5\%) participants had ischemic stroke and 395 (6.7\%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95\% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95\% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95\% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95\% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95\% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95\% CI, -0.07 to 0.11; P = .69).

Conclusions and Relevance: In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.

}, keywords = {Activities of Daily Living, Aged, Brain Ischemia, Cohort Studies, Disabled Persons, Disease Progression, Female, Humans, Male, Myocardial Infarction, Prospective Studies, Stroke}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2017.2802}, author = {Dhamoon, Mandip S and Longstreth, W T and Bartz, Traci M and Kaplan, Robert C and Elkind, Mitchell S V} } @article {7352, title = {Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Apr 21}, pages = {e1006719}, abstract = {

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5{\texttimes}10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5\%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained <= 20 variants in the credible sets that jointly account for 99\% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006719}, author = {Ng, Maggie C Y and Graff, Mariaelisa and Lu, Yingchang and Justice, Anne E and Mudgal, Poorva and Liu, Ching-Ti and Young, Kristin and Yanek, Lisa R and Feitosa, Mary F and Wojczynski, Mary K and Rand, Kristin and Brody, Jennifer A and Cade, Brian E and Dimitrov, Latchezar and Duan, Qing and Guo, Xiuqing and Lange, Leslie A and Nalls, Michael A and Okut, Hayrettin and Tajuddin, Salman M and Tayo, Bamidele O and Vedantam, Sailaja and Bradfield, Jonathan P and Chen, Guanjie and Chen, Wei-Min and Chesi, Alessandra and Irvin, Marguerite R and Padhukasahasram, Badri and Smith, Jennifer A and Zheng, Wei and Allison, Matthew A and Ambrosone, Christine B and Bandera, Elisa V and Bartz, Traci M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Bottinger, Erwin P and Carpten, John and Chanock, Stephen J and Chen, Yii-Der Ida and Conti, David V and Cooper, Richard S and Fornage, Myriam and Freedman, Barry I and Garcia, Melissa and Goodman, Phyllis J and Hsu, Yu-Han H and Hu, Jennifer and Huff, Chad D and Ingles, Sue A and John, Esther M and Kittles, Rick and Klein, Eric and Li, Jin and McKnight, Barbara and Nayak, Uma and Nemesure, Barbara and Ogunniyi, Adesola and Olshan, Andrew and Press, Michael F and Rohde, Rebecca and Rybicki, Benjamin A and Salako, Babatunde and Sanderson, Maureen and Shao, Yaming and Siscovick, David S and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Vaidya, Dhananjay and Witte, John S and Yao, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zonderman, Alan B and Adeyemo, Adebowale and Ambs, Stefan and Cushman, Mary and Faul, Jessica D and Hakonarson, Hakon and Levin, Albert M and Nathanson, Katherine L and Ware, Erin B and Weir, David R and Zhao, Wei and Zhi, Degui and Arnett, Donna K and Grant, Struan F A and Kardia, Sharon L R and Oloapde, Olufunmilayo I and Rao, D C and Rotimi, Charles N and Sale, Mich{\`e}le M and Williams, L Keoki and Zemel, Babette S and Becker, Diane M and Borecki, Ingrid B and Evans, Michele K and Harris, Tamara B and Hirschhorn, Joel N and Li, Yun and Patel, Sanjay R and Psaty, Bruce M and Rotter, Jerome I and Wilson, James G and Bowden, Donald W and Cupples, L Adrienne and Haiman, Christopher A and Loos, Ruth J F and North, Kari E} } @article {7346, title = {Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations.}, journal = {J Lipid Res}, year = {2017}, month = {2017 Mar 15}, abstract = {

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

}, issn = {1539-7262}, doi = {10.1194/jlr.P071860}, author = {Hu, Yao and Tanaka, Toshiko and Zhu, Jingwen and Guan, Weihua and Wu, Jason H Y and Psaty, Bruce M and McKnight, Barbara and King, Irena B and Sun, Qi and Richard, Melissa and Manichaikul, Ani and Frazier-Wood, Alexis C and Kabagambe, Edmond K and Hopkins, Paul N and Ordovas, Jose M and Ferrucci, Luigi and Bandinelli, Stefania and Arnett, Donna K and Chen, Yii-der I and Liang, Shuang and Siscovick, David S and Tsai, Michael Y and Rich, Stephen S and Fornage, Myriam and Hu, Frank B and Rimm, Eric B and Jensen, Majken K and Lemaitre, Rozenn N and Mozaffarian, Dariush and Steffen, Lyn M and Morris, Andrew P and Li, Huaixing and Lin, Xu} } @article {7566, title = {Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.}, journal = {BioData Min}, volume = {10}, year = {2017}, month = {2017}, pages = {25}, abstract = {

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n~=~12,853 to n~=~16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p~<~0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p~<~0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

}, issn = {1756-0381}, doi = {10.1186/s13040-017-0145-5}, author = {Holzinger, Emily R and Verma, Shefali S and Moore, Carrie B and Hall, Molly and De, Rishika and Gilbert-Diamond, Diane and Lanktree, Matthew B and Pankratz, Nathan and Amuzu, Antoinette and Burt, Amber and Dale, Caroline and Dudek, Scott and Furlong, Clement E and Gaunt, Tom R and Kim, Daniel Seung and Riess, Helene and Sivapalaratnam, Suthesh and Tragante, Vinicius and van Iperen, Erik P A and Brautbar, Ariel and Carrell, David S and Crosslin, David R and Jarvik, Gail P and Kuivaniemi, Helena and Kullo, Iftikhar J and Larson, Eric B and Rasmussen-Torvik, Laura J and Tromp, Gerard and Baumert, Jens and Cruickshanks, Karen J and Farrall, Martin and Hingorani, Aroon D and Hovingh, G K and Kleber, Marcus E and Klein, Barbara E and Klein, Ronald and Koenig, Wolfgang and Lange, Leslie A and Mӓrz, Winfried and North, Kari E and Charlotte Onland-Moret, N and Reiner, Alex P and Talmud, Philippa J and van der Schouw, Yvonne T and Wilson, James G and Kivimaki, Mika and Kumari, Meena and Moore, Jason H and Drenos, Fotios and Asselbergs, Folkert W and Keating, Brendan J and Ritchie, Marylyn D} } @article {7363, title = {Discovery of novel heart rate-associated loci using the Exome Chip.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9\% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx113}, author = {van den Berg, Marten E and Warren, Helen R and Cabrera, Claudia P and Verweij, Niek and Mifsud, Borbala and Haessler, Jeffrey and Bihlmeyer, Nathan A and Fu, Yi-Ping and Weiss, Stefan and Lin, Henry J and Grarup, Niels and Li-Gao, Ruifang and Pistis, Giorgio and Shah, Nabi and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Lin, Honghuang and Mei, Hao and Smith, Albert V and Lyytik{\"a}inen, Leo-Pekka and Hall, Leanne M and van Setten, Jessica and Trompet, Stella and Prins, Bram P and Isaacs, Aaron and Radmanesh, Farid and Marten, Jonathan and Entwistle, Aiman and Kors, Jan A and Silva, Claudia T and Alonso, Alvaro and Bis, Joshua C and de Boer, Rudolf and de Haan, Hugoline G and de Mutsert, Ren{\'e}e and Dedoussis, George and Dominiczak, Anna F and Doney, Alex S F and Ellinor, Patrick T and Eppinga, Ruben N and Felix, Stephan B and Guo, Xiuqing and Hagemeijer, Yanick and Hansen, Torben and Harris, Tamara B and Heckbert, Susan R and Huang, Paul L and Hwang, Shih-Jen and K{\"a}h{\"o}nen, Mika and Kanters, J{\o}rgen K and Kolcic, Ivana and Launer, Lenore J and Li, Man and Yao, Jie and Linneberg, Allan and Liu, Simin and Macfarlane, Peter W and Mangino, Massimo and Morris, Andrew D and Mulas, Antonella and Murray, Alison D and Nelson, Christopher P and Orr{\`u}, Marco and Padmanabhan, Sandosh and Peters, Annette and Porteous, David J and Poulter, Neil and Psaty, Bruce M and Qi, Lihong and Raitakari, Olli T and Rivadeneira, Fernando and Roselli, Carolina and Rudan, Igor and Sattar, Naveed and Sever, Peter and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Timothy D and Stanton, Alice V and Stirrups, Kathleen E and Taylor, Kent D and Tobin, Martin D and Uitterlinden, Andre and Vaartjes, Ilonca and Hoes, Arno W and van der Meer, Peter and V{\"o}lker, Uwe and Waldenberger, Melanie and Xie, Zhijun and Zoledziewska, Magdalena and Tinker, Andrew and Polasek, Ozren and Rosand, Jonathan and Jamshidi, Yalda and van Duijn, Cornelia M and Zeggini, Eleftheria and Wouter Jukema, J and Asselbergs, Folkert W and Samani, Nilesh J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Wilson, James and Lubitz, Steven A and K{\"a}{\"a}b, Stefan and Sotoodehnia, Nona and Caulfield, Mark J and Palmer, Colin N A and Sanna, Serena and Mook-Kanamori, Dennis O and Deloukas, Panos and Pedersen, Oluf and Rotter, Jerome I and D{\"o}rr, Marcus and O{\textquoteright}Donnell, Chris J and Hayward, Caroline and Arking, Dan E and Kooperberg, Charles and van der Harst, Pim and Eijgelsheim, Mark and Stricker, Bruno H and Munroe, Patricia B} } @article {7583, title = {DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Dec 07}, pages = {888-902}, abstract = {

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0~{\texttimes} 10-7; replication: N = 7,182, p~<~1.6~{\texttimes} 10-3). The replicated methylation sites are heritable (h2 > 30\%) and independent of known BP genetic variants, explaining an additional 1.4\% and 2.0\% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

}, keywords = {Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.028}, author = {Richard, Melissa A and Huan, Tianxiao and Ligthart, Symen and Gondalia, Rahul and Jhun, Min A and Brody, Jennifer A and Irvin, Marguerite R and Marioni, Riccardo and Shen, Jincheng and Tsai, Pei-Chien and Montasser, May E and Jia, Yucheng and Syme, Catriona and Salfati, Elias L and Boerwinkle, Eric and Guan, Weihua and Mosley, Thomas H and Bressler, Jan and Morrison, Alanna C and Liu, Chunyu and Mendelson, Michael M and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B and Franco, Oscar H and Zhang, Guosheng and Li, Yun and Stewart, James D and Bis, Joshua C and Psaty, Bruce M and Chen, Yii-Der Ida and Kardia, Sharon L R and Zhao, Wei and Turner, Stephen T and Absher, Devin and Aslibekyan, Stella and Starr, John M and McRae, Allan F and Hou, Lifang and Just, Allan C and Schwartz, Joel D and Vokonas, Pantel S and Menni, Cristina and Spector, Tim D and Shuldiner, Alan and Damcott, Coleen M and Rotter, Jerome I and Palmas, Walter and Liu, Yongmei and Paus, Tom{\'a}{\v s} and Horvath, Steve and O{\textquoteright}Connell, Jeffrey R and Guo, Xiuqing and Pausova, Zdenka and Assimes, Themistocles L and Sotoodehnia, Nona and Smith, Jennifer A and Arnett, Donna K and Deary, Ian J and Baccarelli, Andrea A and Bell, Jordana T and Whitsel, Eric and Dehghan, Abbas and Levy, Daniel and Fornage, Myriam} } @article {8536, title = {{Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies}, journal = {Clin Chem}, volume = {64}, year = {2018}, month = {01}, pages = {183{\textendash}191}, abstract = {Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.\ We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.\ Higher dairy intake was associated with higher BMI ({\^I}{\texttwosuperior} = 0.03 kg/m2 per serving/day; 95\% CI, 0.00-0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95\% CI, 0.14-0.25) serving/day higher dairy intake (P = 3.15 {\~A}{\textemdash} 10-12) and 0.12 (95\% CI, 0.06-0.17) kg/m2 higher BMI (P = 2.11 {\~A}{\textemdash} 10-5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI ({\^I}{\texttwosuperior} = 0.60 kg/m2 per serving/day; 95\% CI, 0.27-0.92; P = 3.0 {\~A}{\textemdash} 10-4).\ The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.}, author = {Huang, T. and Ding, M. and Bergholdt, H. K. M. and Wang, T. and Heianza, Y. and Sun, D. and Frazier-Wood, A. C. and Aslibekyan, S. and North, K. E. and Voortman, T. and Graff, M. and Smith, C. E. and Lai, C. Q. and Varbo, A. and Lemaitre, R. N. and de Jonge, M. E. A. L. and Fumeron, F. and Corella, D. and Wang, C. A. and Tj?nneland, A. and Overvad, K. and S?rensen, T. I. A. and Feitosa, M. F. and Wojczynski, M. K. and K?h?nen, M. and Renstr?m, F. and Psaty, B. M. and Siscovick, D. S. and Barroso, I. and Johansson, I. and Hernandez, D. and Ferrucci, L. and Bandinelli, S. and Linneberg, A. and Zillikens, M. C. and Sandholt, C. H. and Pedersen, O. and Hansen, T. and Schulz, C. A. and Sonestedt, E. and Orho-Melander, M. and Chen, T. A. and Rotter, J. I. and Allison, M. A. and Rich, S. S. and Sorl?, J. V. and Coltell, O. and Pennell, C. E. and Eastwood, P. and Hofman, A. and Uitterlinden, A. G. and van Rooij, F. J. A. and Chu, A. Y. and Rose, L. M. and Ridker, P. M. and Viikari, J. and Raitakari, O. and Lehtim?ki, T. and Mikkil?, V. and Willett, W. C. and Wang, Y. and Tucker, K. L. and Ordovas, J. M. and Kilpel?inen, T. O. and Province, M. A. and Franks, P. W. and Arnett, D. K. and Tanaka, T. and Toft, U. and Ericson, U. and Franco, O. H. and Mozaffarian, D. and Hu, F. B. and Chasman, D. I. and Nordestgaard, B. G. and Ellervik, C. and Qi, L.} } @article {8043, title = {Demographic-Specific Rates for Life Events in the Cardiovascular Health Study and Comparisons With Other Studies.}, journal = {Innov Aging}, volume = {2}, year = {2018}, month = {2018 Jan}, pages = {igy005}, abstract = {

Purpose of the Study: (1a) We use the Cardiovascular Health Study (CHS), a multi-site heterogeneous sample of Medicare enrollees ( = 5,849) to provide rates for specific life events experienced within 6 months; (1b) We present rates for 29 other studies of community-residing older adults ( = 41,308); (2) For the CHS, we provide demographic-specific rates and predicted probabilities for age [young-old (65-75) vs old-old (>=75)], gender, race, marital status, and education.

Design/Methods: The CHS sample is 57.6\% women, 84.2\% white (15.8\% black), and 66.3\% married. Mean age is 72.8 years (standard deviation [] = 5.6, range = 65-100) and education is 13.7 years ( = 4.8). Life events were interviewer-assessed. Regressions estimated associations of life event rates with demographic groups (e.g., age), controlling for other demographic variables (e.g., gender, etc.).

Results: (1a) CHS rates ranged from 44.7\% (death of someone close) to 1.1\% (retirement/work changes). (1b) Most life event studies used total scores and only 5 that met our inclusion criteria used time intervals <1 year; longer intervals were associated with higher rates. (2) In the CHS, the life event for illnesses was related to 5 demographic variables (net the other 4 demographic variables), difficulties caregiving to 4, and worse relationships to 3 demographic variables. Race was related to 8 life events, marital status to 7, education to 6, and age to 4 events.

Implications: By identifying demographic groups at highest risk for life events, this research focuses on older adults at greatest risk for health problems. These data are necessary for translating research into interventions, practice, and policy.

}, issn = {2399-5300}, doi = {10.1093/geroni/igy005}, author = {Vitaliano, Peter P and Fitzpatrick, Annette L and Williams, Lee E and Montano, Michalina A and Russo, Joan E} } @article {7662, title = {Development, Construct Validity, and Predictive Validity of a Continuous Frailty Scale: Results from Two Large U.S. Cohorts.}, journal = {Am J Epidemiol}, year = {2018}, month = {2018 Apr 24}, abstract = {

Frailty is an age-related clinical syndrome of decreased resilience to stressors. Among numerous assessments of frailty, the frailty phenotype (FP) scale, proposed by Fried and colleagues has been the most widely used one. We aimed to develop a continuous frailty scale that may overcome limitations facing the categorical FP scale and to evaluate its construct validity, predictive validity, and measurement properties. Data were from the Cardiovascular Health Study (N~=~4243) and Health and Retirement Study (N~=~7600). Frailty was conceptualized as a continuous construct, measured by five measures used in FP scale: gait speed, grip strength, exhaustion, physical activity, and weight loss. We used confirmatory factor analysis to investigate the relationship between five indicators and the latent frailty construct. We examined the association of the continuous frailty scale with mortality and disability. The unidimensional model fit the data satisfactorily; similar factor structure was observed across two cohorts. Gait speed and weight loss were the strongest and weakest indicators, respectively; grip strength, exhaustion, and physical activity had similar strength in measuring frailty. In each cohort, the continuous frailty scale was strongly associated with mortality and disability and persisted to be associated with outcomes among robust and prefrail persons classified by the FP scale.

}, issn = {1476-6256}, doi = {10.1093/aje/kwy041}, author = {Wu, Chenkai and Geldhof, G John and Xue, Qian-Li and Kim, Dae H and Newman, Anne B and Odden, Michelle C} } @article {7798, title = {Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 Aug 15}, pages = {2940-2953}, abstract = {

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30~503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and \~{}200~000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddy211}, author = {Kocarnik, Jonathan M and Richard, Melissa and Graff, Misa and Haessler, Jeffrey and Bien, Stephanie and Carlson, Chris and Carty, Cara L and Reiner, Alexander P and Avery, Christy L and Ballantyne, Christie M and LaCroix, Andrea Z and Assimes, Themistocles L and Barbalic, Maja and Pankratz, Nathan and Tang, Weihong and Tao, Ran and Chen, Dongquan and Talavera, Gregory A and Daviglus, Martha L and Chirinos-Medina, Diana A and Pereira, Rocio and Nishimura, Katie and B{\r u}zkov{\'a}, Petra and Best, Lyle G and Ambite, Jose Luis and Cheng, Iona and Crawford, Dana C and Hindorff, Lucia A and Fornage, Myriam and Heiss, Gerardo and North, Kari E and Haiman, Christopher A and Peters, Ulrike and Le Marchand, Lo{\"\i}c and Kooperberg, Charles} } @article {7816, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.}, journal = {Blood}, year = {2018}, month = {2018 Jul 24}, abstract = {

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K and Huffman, Jennifer E and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W David and Jhun, Min A and Brody, Jennifer A and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S and de Vries, Paul S and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C and Boerwinkle, Eric and Wiggins, Kerri L and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M and Sotoodenia, Nona and Boomsa, Dorret I and Willemsen, Gonneke and Ligthart, Lannie and Deary, Ian J and Zhao, Wei and Ware, Erin B and Kardia, Sharon L R and van Meurs, Joyce B J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S and Johnson, Andrew D and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J C and Starr, John M and Smith, Jennifer A and Dehghan, Abbas and Bj{\"o}rck, Hanna M and Smith, Nicholas L and Peters, Annette} } @article {8107, title = {Dairy Intake and Body Composition and Cardiometabolic Traits among Adults: Mendelian Randomization Analysis of 182041 Individuals from 18 Studies.}, journal = {Clin Chem}, volume = {65}, year = {2019}, month = {2019 Jun}, pages = {751-760}, abstract = {

BACKGROUND: Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined.

METHODS: We performed Mendelian randomization analysis using an established genetic variant located upstream of the lactase gene (-13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies.

RESULTS: Each 1 serving/day higher dairy intake was associated with higher lean mass [β (SE) = 0.117 kg (0.035); = 0.001], higher hemoglobin A [0.009\% (0.002); < 0.001], lower LDL [-0.014 mmol/L (0.006); = 0.013], total cholesterol (TC) [-0.012 mmol/L (0.005); = 0.023], and non-HDL [-0.012 mmol/L (0.005); = 0.028]. The -13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; < 0.001), 0.284 cm higher waist circumference (SE = 0.118; = 0.017), 0.112 kg higher lean mass (SE = 0.027; = 3.8 {\texttimes} 10), 0.032 mmol/L lower LDL (SE = 0.009; = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits.

CONCLUSIONS: The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding.

}, issn = {1530-8561}, doi = {10.1373/clinchem.2018.300335} } @article {7982, title = {Discrepancy in Frailty Identification: Move beyond Predictive Validity.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2019}, month = {2019 Feb 21}, abstract = {

BACKGROUND: To evaluate the discordance in frailty classification between the frailty index (FI) and the physical frailty phenotype (PFP) and identify factors discriminating those with discordant frailty classification from each other and from those for whom the assessments agree.

METHODS: A prospective observational study of older adults aged 65 and older selected from Medicare eligibility lists in four US communities (n=5,362). The PFP was measured by the Cardiovascular Health Study PFP. Subjects meeting >=3 of the 5 criteria were deemed frail. The FI was calculated as the proportion of deficits in an a priori selected set of 48 measures and subjects were classified as frail if FI>0.35.

RESULTS: The prevalence of frailty was 7.0\% by the PFP and 8.3\% by the FI. Of the 730 deemed frail by either instrument, only 12\% were in agreement; whereas 39\% were classified as frail by PFP but not FI; and 48\% were classified as frail by FI but not PFP. Participants aged 65-72 or greater disease burden were mostly likely to be characterized as being FI-frail but not PFP-frail. The associations of frailty with age and mortality was stronger when frailty was measured by the PFP rather than the FI.

CONCLUSIONS: Despite comparable frailty prevalence between the PFP and the FI, there was substantial discordance in individual-level classification, with highest agreement existing only in the most vulnerable subset. These findings suggest that there are clinically important contexts in which PFP and FI cannot be used interchangeably.

}, issn = {1758-535X}, doi = {10.1093/gerona/glz052}, author = {Xue, Qian-Li and Tian, Jing and Walston, Jeremy D and Chaves, Paulo H M and Newman, Anne B and Bandeen-Roche, Karen} } @article {8097, title = {Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality.}, journal = {JAMA}, volume = {321}, year = {2019}, month = {2019 06 25}, pages = {2438-2447}, abstract = {

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.

Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.

Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).

Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.

Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54\%] women; 16 794 [69\%] non-Hispanic white; 15 181 [63\%] ever smokers), complete follow-up was available for 11 077 (77\%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95\% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95\% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.

Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Female, Forced Expiratory Volume, Hospitalization, Humans, Male, Middle Aged, Prognosis, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive, Risk Assessment, Vital Capacity}, issn = {1538-3598}, doi = {10.1001/jama.2019.7233}, author = {Bhatt, Surya P and Balte, Pallavi P and Schwartz, Joseph E and Cassano, Patricia A and Couper, David and Jacobs, David R and Kalhan, Ravi and O{\textquoteright}Connor, George T and Yende, Sachin and Sanders, Jason L and Umans, Jason G and Dransfield, Mark T and Chaves, Paulo H and White, Wendy B and Oelsner, Elizabeth C} } @article {7974, title = {Disentangling the genetics of lean mass.}, journal = {Am J Clin Nutr}, volume = {109}, year = {2019}, month = {2019 Feb 01}, pages = {276-287}, abstract = {

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n~=~38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy272}, author = {Karasik, David and Zillikens, M Carola and Hsu, Yi-Hsiang and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Bochud, Murielle and Borecki, Ingrid B and Broer, Linda and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos-Obando, Natalia and Cauley, Jane A and Cawthon, Peggy M and Chambers, John C and Chen, Zhao and Cho, Nam H and Choi, Hyung Jin and Chou, Wen-Chi and Cummings, Steven R and de Groot, Lisette C P G M and De Jager, Phillip L and Demuth, Ilja and Diatchenko, Luda and Econs, Michael J and Eiriksdottir, Gudny and Enneman, Anke W and Eriksson, Joel and Eriksson, Johan G and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Gieger, Christian and Grallert, Harald and Gudnason, Vilmundur and Lenore, Launer J and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Johnson, Toby and Biffar, Reiner and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koller, Daniel L and Kooner, Jaspal S and Kraus, William E and Kritchevsky, Stephen and Kutalik, Zolt{\'a}n and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Lerch, Markus M and Lewis, Joshua R and Lill, Christina and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Livshits, Gregory and Ljunggren, Osten and Loos, Ruth J F and Lorentzon, Mattias and Luan, Jian{\textquoteright}an and Luben, Robert N and Malkin, Ida and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Nethander, Maria and Newman, Anne B and O{\textquoteright}Connell, Jeffery R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Peacock, Munro and Perola, Markus and Peters, Annette and Prince, Richard L and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Rivadeneira, Fernando and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schipf, Sabine and Shin, Chan Soo and Smith, Albert V and Smith, Shad B and Soranzo, Nicole and Spector, Timothy D and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Kari and Steinhagen-Thiessen, Elisabeth and Stolk, Lisette and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Thompson, Patricia and Thomson, Cynthia A and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and van Schoor, Natasja M and Vandenput, Liesbeth and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and J Wareham, Nicholas and Waterworth, Dawn and Weedon, Michael N and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Yerges-Armstrong, Laura M and Yu, Lei and Zhang, Weihua and Zhao, Jing Hua and Zhou, Yanhua and Nielson, Carrie M and Harris, Tamara B and Demissie, Serkalem and Kiel, Douglas P and Ohlsson, Claes} } @article {8404, title = {The Difference Between Cystatin C and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS).}, journal = {Am J Kidney Dis}, year = {2020}, month = {2020 Jul 09}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2020.05.018}, author = {Potok, O Alison and Phil, Ronit Katz D and Bansal, Nisha and Siscovick, David S and Odden, Michelle and Ix, Joachim H and Shlipak, Michael G and Rifkin, Dena E} } @article {8636, title = {{Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {12}, pages = {1314{\textendash}1332}, abstract = {Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency {\^a}{\textperthousand}¤ 0.01) variant BP associations (P < 5 {\~A}{\textemdash} 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44\% coding) were 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.}, author = {Surendran, P. and Feofanova, E. V. and Lahrouchi, N. and Ntalla, I. and Karthikeyan, S. and Cook, J. and Chen, L. and Mifsud, B. and Yao, C. and Kraja, A. T. and Cartwright, J. H. and Hellwege, J. N. and Giri, A. and Tragante, V. and Thorleifsson, G. and Liu, D. J. and Prins, B. P. and Stewart, I. D. and Cabrera, C. P. and Eales, J. M. and Akbarov, A. and Auer, P. L. and Bielak, L. F. and Bis, J. C. and Braithwaite, V. S. and Brody, J. A. and Daw, E. W. and Warren, H. R. and Drenos, F. and Nielsen, S. F. and Faul, J. D. and Fauman, E. B. and Fava, C. and Ferreira, T. and Foley, C. N. and Franceschini, N. and Gao, H. and Giannakopoulou, O. and Giulianini, F. and Gudbjartsson, D. F. and Guo, X. and Harris, S. E. and Havulinna, A. S. and Helgadottir, A. and Huffman, J. E. and Hwang, S. J. and Kanoni, S. and Kontto, J. and Larson, M. G. and Li-Gao, R. and Lindstr?m, J. and Lotta, L. A. and Lu, Y. and Luan, J. and Mahajan, A. and Malerba, G. and Masca, N. G. D. and Mei, H. and Menni, C. and Mook-Kanamori, D. O. and Mosen-Ansorena, D. and M?ller-Nurasyid, M. and Par?, G. and Paul, D. S. and Perola, M. and Poveda, A. and Rauramaa, R. and Richard, M. and Richardson, T. G. and Sep?lveda, N. and Sim, X. and Smith, A. V. and Smith, J. A. and Staley, J. R. and Stan?kov?, A. and Sulem, P. and Th?riault, S. and Thorsteinsdottir, U. and Trompet, S. and Varga, T. V. and Velez Edwards, D. R. and Veronesi, G. and Weiss, S. and Willems, S. M. and Yao, J. and Young, R. and Yu, B. and Zhang, W. and Zhao, J. H. and Zhao, W. and Zhao, W. and Evangelou, E. and Aeschbacher, S. and Asllanaj, E. and Blankenberg, S. and Bonnycastle, L. L. and Bork-Jensen, J. and Brandslund, I. and Braund, P. S. and Burgess, S. and Cho, K. and Christensen, C. and Connell, J. and Mutsert, R. and Dominiczak, A. F. and D?rr, M. and Eiriksdottir, G. and Farmaki, A. E. and Gaziano, J. M. and Grarup, N. and Grove, M. L. and Hallmans, G. and Hansen, T. and Have, C. T. and Heiss, G. and J?rgensen, M. E. and Jousilahti, P. and Kajantie, E. and Kamat, M. and K?r?j?m?ki, A. and Karpe, F. and Koistinen, H. A. and Kovesdy, C. P. and Kuulasmaa, K. and Laatikainen, T. and Lannfelt, L. and Lee, I. T. and Lee, W. J. and Linneberg, A. and Martin, L. W. and Moitry, M. and Nadkarni, G. and Neville, M. J. and Palmer, C. N. A. and Papanicolaou, G. J. and Pedersen, O. and Peters, J. and Poulter, N. and Rasheed, A. and Rasmussen, K. L. and Rayner, N. W. and M?gi, R. and Renstr?m, F. and Rettig, R. and Rossouw, J. and Schreiner, P. J. and Sever, P. S. and Sigurdsson, E. L. and Skaaby, T. and Sun, Y. V. and Sundstrom, J. and Thorgeirsson, G. and Esko, T. and Trabetti, E. and Tsao, P. S. and Tuomi, T. and Turner, S. T. and Tzoulaki, I. and Vaartjes, I. and Vergnaud, A. C. and Willer, C. J. and Wilson, P. W. F. and Witte, D. R. and Yonova-Doing, E. and Zhang, H. and Aliya, N. and Almgren, P. and Amouyel, P. and Asselbergs, F. W. and Barnes, M. R. and Blakemore, A. I. and Boehnke, M. and Bots, M. L. and Bottinger, E. P. and Buring, J. E. and Chambers, J. C. and Chen, Y. I. and Chowdhury, R. and Conen, D. and Correa, A. and Davey Smith, G. and Boer, R. A. and Deary, I. J. and Dedoussis, G. and Deloukas, P. and Di Angelantonio, E. and Elliott, P. and Felix, S. B. and Ferri?res, J. and Ford, I. and Fornage, M. and Franks, P. W. and Franks, S. and Frossard, P. and Gambaro, G. and Gaunt, T. R. and Groop, L. and Gudnason, V. and Harris, T. B. and Hayward, C. and Hennig, B. J. and Herzig, K. H. and Ingelsson, E. and Tuomilehto, J. and J?rvelin, M. R. and Jukema, J. W. and Kardia, S. L. R. and Kee, F. and Kooner, J. S. and Kooperberg, C. and Launer, L. J. and Lind, L. and Loos, R. J. F. and Majumder, A. A. S. and Laakso, M. and McCarthy, M. I. and Melander, O. and Mohlke, K. L. and Murray, A. D. and Nordestgaard, B. G. and Orho-Melander, M. and Packard, C. J. and Padmanabhan, S. and Palmas, W. and Polasek, O. and Porteous, D. J. and Prentice, A. M. and Province, M. A. and Relton, C. L. and Rice, K. and Ridker, P. M. and Rolandsson, O. and Rosendaal, F. R. and Rotter, J. I. and Rudan, I. and Salomaa, V. and Samani, N. J. and Sattar, N. and Sheu, W. H. and Smith, B. H. and Soranzo, N. and Spector, T. D. and Starr, J. M. and Sebert, S. and Taylor, K. D. and Lakka, T. A. and Timpson, N. J. and Tobin, M. D. and van der Harst, P. and van der Meer, P. and Ramachandran, V. S. and Verweij, N. and Virtamo, J. and V?lker, U. and Weir, D. R. and Zeggini, E. and Charchar, F. J. and Wareham, N. J. and Langenberg, C. and Tomaszewski, M. and Butterworth, A. S. and Caulfield, M. J. and Danesh, J. and Edwards, T. L. and Holm, H. and Hung, A. M. and Lindgren, C. M. and Liu, C. and Manning, A. K. and Morris, A. P. and Morrison, A. C. and O{\textquoteright}Donnell, C. J. and Psaty, B. M. and Saleheen, D. and Stefansson, K. and Boerwinkle, E. and Chasman, D. I. and Levy, D. and Newton-Cheh, C. and Munroe, P. B. and Howson, J. M. M. and de Boer, R. A. and van der Harst, P. and van der Meer, P. and Verweij, N. and Butterworth, A. S. and Danesh, J. and Langenberg, C. and Deloukas, P. and McCarthy, M. I. and Franks, P. W. and Rolandsson, O. and Wareham, N. J. and Prins, B. P. and Zeggini, E. and Hellwege, J. N. and Giri, A. and Edwards, D. R. V. and Cho, K. and Gaziano, J. M. and Kovesdy, C. P. and Sun, Y. V. and Tsao, P. S. and Wilson, P. W. F. and Edwards, T. L. and Hung, A. M. and O{\textquoteright}Donnell, C. J.} } @article {8623, title = {A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.}, journal = {Am J Epidemiol}, volume = {189}, year = {2020}, month = {2020 10 01}, pages = {1173-1184}, abstract = {

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at >=3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and~-0.24\%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r~=~-0.16) and FVC (r~=~-0.26) and slower declines in FEV1:FVC ratio (r~=~0.11) (all P~values <~0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P~<~0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

}, keywords = {Adult, Aged, Body Mass Index, Cohort Studies, Humans, Linear Models, Lung, Middle Aged, Respiratory Function Tests, Weight Gain}, issn = {1476-6256}, doi = {10.1093/aje/kwaa059}, author = {Cornelius, Talea and Schwartz, Joseph E and Balte, Pallavi and Bhatt, Surya P and Cassano, Patricia A and Currow, David and Jacobs, David R and Johnson, Miriam and Kalhan, Ravi and Kronmal, Richard and Loehr, Laura and O{\textquoteright}Connor, George T and Smith, Benjamin and White, Wendy B and Yende, Sachin and Oelsner, Elizabeth C} } @article {8453, title = {{Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {Sep}, pages = {969{\textendash}983}, abstract = {Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce {\textquoteright}annotation principal components{\textquoteright}, multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.}, author = {Li, X. and Li, Z. and Zhou, H. and Gaynor, S. M. and Liu, Y. and Chen, H. and Sun, R. and Dey, R. and Arnett, D. K. and Aslibekyan, S. and Ballantyne, C. M. and Bielak, L. F. and Blangero, J. and Boerwinkle, E. and Bowden, D. W. and Broome, J. G. and Conomos, M. P. and Correa, A. and Cupples, L. A. and Curran, J. E. and Freedman, B. I. and Guo, X. and Hindy, G. and Irvin, M. R. and Kardia, S. L. R. and Kathiresan, S. and Khan, A. T. and Kooperberg, C. L. and Laurie, C. C. and Liu, X. S. and Mahaney, M. C. and Manichaikul, A. W. and Martin, L. W. and Mathias, R. A. and McGarvey, S. T. and Mitchell, B. D. and Montasser, M. E. and Moore, J. E. and Morrison, A. C. and O{\textquoteright}Connell, J. R. and Palmer, N. D. and Pampana, A. and Peralta, J. M. and Peyser, P. A. and Psaty, B. M. and Redline, S. and Rice, K. M. and Rich, S. S. and Smith, J. A. and Tiwari, H. K. and Tsai, M. Y. and Vasan, R. S. and Wang, F. F. and Weeks, D. E. and Weng, Z. and Wilson, J. G. and Yanek, L. R. and Neale, B. M. and Sunyaev, S. R. and Abecasis, G. R. and Rotter, J. I. and Willer, C. J. and Peloso, G. M. and Natarajan, P. and Lin, X. and Abe, N. and Abecasis, G. R. and Aguet, F. and Albert, C. and Almasy, L. and Alonso, A. and Ament, S. and Anderson, P. and Anugu, P. and Applebaum-Bowden, D. and Ardlie, K. and Arking, D. and Arnett, D. K. and Ashley-Koch, A. and Aslibekyan, S. and Assimes, T. and Auer, P. and Avramopoulos, D. and Barnard, J. and Barnes, K. and Barr, R. G. and Barron-Casella, E. and Barwick, L. and Beaty, T. and Beck, G. and Becker, D. and Becker, L. and Beer, R. and Beitelshees, A. and Benjamin, E. and Benos, T. and Bezerra, M. and Bielak, L. F. and Bis, J. and Blackwell, T. and Blangero, J. and Boerwinkle, E. and Bowden, D. W. and Bowler, R. and Brody, J. and Broeckel, U. and Broome, J. G. and Bunting, K. and Burchard, E. and Bustamante, C. and Buth, E. and Cade, B. and Cardwell, J. and Carey, V. and Carty, C. and Casaburi, R. and Casella, J. and Castaldi, P. and Chaffin, M. and Chang, C. and Chang, Y. C. and Chasman, D. and Chavan, S. and Chen, B. J. and Chen, W. M. and Chen, Y. I. and Cho, M. and Choi, S. H. and Chuang, L. M. and Chung, M. and Chung, R. H. and Clish, C. and Comhair, S. and Conomos, M. P. and Cornell, E. and Correa, A. and Crandall, C. and Crapo, J. and Cupples, L. A. and Curran, J. E. and Curtis, J. and Custer, B. and Damcott, C. and Darbar, D. and Das, S. and David, S. and Davis, C. and Daya, M. and de Andrade, M. and Fuentes, L. L. and DeBaun, M. and Deka, R. and DeMeo, D. and Devine, S. and Duan, Q. and Duggirala, R. and Durda, J. P. and Dutcher, S. and Eaton, C. and Ekunwe, L. and El Boueiz, A. and Ellinor, P. and Emery, L. and Erzurum, S. and Farber, C. and Fingerlin, T. and Flickinger, M. and Fornage, M. and Franceschini, N. and Frazar, C. and Fu, M. and Fullerton, S. M. and Fulton, L. and Gabriel, S. and Gan, W. and Gao, S. and Gao, Y. and Gass, M. and Gelb, B. and Geng, X. P. and Geraci, M. and Germer, S. and Gerszten, R. and Ghosh, A. and Gibbs, R. and Gignoux, C. and Gladwin, M. and Glahn, D. and Gogarten, S. and Gong, D. W. and Goring, H. and Graw, S. and Grine, D. and Gu, C. C. and Guan, Y. and Guo, X. and Gupta, N. and Haessler, J. and Hall, M. and Harris, D. and Hawley, N. L. and He, J. and Heckbert, S. and Hernandez, R. and Herrington, D. and Hersh, C. and Hidalgo, B. and Hixson, J. and Hobbs, B. and Hokanson, J. and Hong, E. and Hoth, K. and Hsiung, C. A. and Hung, Y. J. and Huston, H. and Hwu, C. M. and Irvin, M. R. and Jackson, R. and Jain, D. and Jaquish, C. and Jhun, M. A. and Johnsen, J. and Johnson, A. and Johnson, C. and Johnston, R. and Jones, K. and Kang, H. M. and Kaplan, R. and Kardia, S. L. R. and Kathiresan, S. and Kelly, S. and Kenny, E. and Kessler, M. and Khan, A. T. and Kim, W. and Kinney, G. and Konkle, B. and Kooperberg, C. L. and Kramer, H. and Lange, C. and Lange, E. and Lange, L. and Laurie, C. C. and Laurie, C. and LeBoff, M. and Lee, J. and Lee, S. S. and Lee, W. J. and LeFaive, J. and Levine, D. and Levy, D. and Lewis, J. and Li, X. and Li, Y. and Lin, H. and Lin, H. and Lin, K. H. and Lin, X. and Liu, S. and Liu, Y. and Liu, Y. and Loos, R. J. F. and Lubitz, S. and Lunetta, K. and Luo, J. and Mahaney, M. C. and Make, B. and Manichaikul, A. W. and Manson, J. and Margolin, L. and Martin, L. W. and Mathai, S. and Mathias, R. A. and May, S. and McArdle, P. and McDonald, M. L. and McFarland, S. and McGarvey, S. T. and McGoldrick, D. and McHugh, C. and Mei, H. and Mestroni, L. and Meyers, D. A. and Mikulla, J. and Min, N. and Minear, M. and Minster, R. L. and Mitchell, B. D. and Moll, M. and Montasser, M. E. and Montgomery, C. and Moscati, A. and Musani, S. and Mwasongwe, S. and Mychaleckyj, J. C. and Nadkarni, G. and Naik, R. and Naseri, T. and Natarajan, P. and Nekhai, S. and Nelson, S. C. and Neltner, B. and Nickerson, D. and North, K. and O{\textquoteright}Connell, J. R. and O{\textquoteright}Connor, T. and Ochs-Balcom, H. and Paik, D. and Palmer, N. D. and Pankow, J. and Papanicolaou, G. and Parsa, A. and Peralta, J. M. and Perez, M. and Perry, J. and Peters, U. and Peyser, P. A. and Phillips, L. S. and Pollin, T. and Post, W. and Becker, J. P. and Boorgula, M. P. and Preuss, M. and Psaty, B. M. and Qasba, P. and Qiao, D. and Qin, Z. and Rafaels, N. and Raffield, L. and Vasan, R. S. and Rao, D. C. and Rasmussen-Torvik, L. and Ratan, A. and Redline, S. and Reed, R. and Regan, E. and Reiner, A. and Reupena, M. S. and Rice, K. M. and Rich, S. S. and Roden, D. and Roselli, C. and Rotter, J. I. and Ruczinski, I. and Russell, P. and Ruuska, S. and Ryan, K. and Sabino, E. C. and Saleheen, D. and Salimi, S. and Salzberg, S. and Sandow, K. and Sankaran, V. G. and Scheller, C. and Schmidt, E. and Schwander, K. and Schwartz, D. and Sciurba, F. and Seidman, C. and Seidman, J. and Sheehan, V. and Sherman, S. L. and Shetty, A. and Shetty, A. and Sheu, W. H. and Shoemaker, M. B. and Silver, B. and Silverman, E. and Smith, J. A. and Smith, J. and Smith, N. and Smith, T. and Smoller, S. and Snively, B. and Snyder, M. and Sofer, T. and Sotoodehnia, N. and Stilp, A. M. and Storm, G. and Streeten, E. and Su, J. L. and Sung, Y. J. and Sylvia, J. and Szpiro, A. and Sztalryd, C. and Taliun, D. and Tang, H. and Taub, M. and Taylor, K. D. and Taylor, M. and Taylor, S. and Telen, M. and Thornton, T. A. and Threlkeld, M. and Tinker, L. and Tirschwell, D. and Tishkoff, S. and Tiwari, H. K. and Tong, C. and Tracy, R. and Tsai, M. Y. and Vaidya, D. and Van Den Berg, D. and VandeHaar, P. and Vrieze, S. and Walker, T. and Wallace, R. and Walts, A. and Wang, F. F. and Wang, H. and Watson, K. and Weeks, D. E. and Weir, B. and Weiss, S. and Weng, L. C. and Wessel, J. and Willer, C. J. and Williams, K. and Williams, L. K. and Wilson, C. and Wilson, J. G. and Wong, Q. and Wu, J. and Xu, H. and Yanek, L. R. and Yang, I. and Yang, R. and Zaghloul, N. and Zekavat, M. and Zhang, Y. and Zhao, S. X. and Zhao, W. and Zhi, D. and Zhou, X. and Zhu, X. and Zody, M. and Zoellner, S. and Abdalla, M. and Abecasis, G. R. and Arnett, D. K. and Aslibekyan, S. and Assimes, T. and Atkinson, E. and Ballantyne, C. M. and Beitelshees, A. and Bielak, L. F. and Bis, J. and Bodea, C. and Boerwinkle, E. and Bowden, D. W. and Brody, J. and Cade, B. and Carlson, J. and Chang, I. S. and Chen, Y. I. and Chun, S. and Chung, R. H. and Conomos, M. P. and Correa, A. and Cupples, L. A. and Damcott, C. and de Vries, P. and Do, R. and Elliott, A. and Fu, M. and Ganna, A. and Gong, D. W. and Graham, S. and Haas, M. and Haring, B. and He, J. and Heckbert, S. and Himes, B. and Hixson, J. and Irvin, M. R. and Jain, D. and Jarvik, G. and Jhun, M. A. and Jiang, J. and Jun, G. and Kalyani, R. and Kardia, S. L. R. and Kathiresan, S. and Khera, A. and Klarin, D. and Kooperberg, C. L. and Kral, B. and Lange, L. and Laurie, C. C. and Laurie, C. and Lemaitre, R. and Li, Z. and Li, X. and Lin, X. and Mahaney, M. C. and Manichaikul, A. W. and Martin, L. W. and Mathias, R. A. and Mathur, R. and McGarvey, S. T. and McHugh, C. and McLenithan, J. and Mikulla, J. and Mitchell, B. D. and Montasser, M. E. and Moran, A. and Morrison, A. C. and Nakao, T. and Natarajan, P. and Nickerson, D. and North, K. and O{\textquoteright}Connell, J. R. and O{\textquoteright}Donnell, C. and Palmer, N. D. and Pampana, A. and Patel, A. and Peloso, G. M. and Perry, J. and Peters, U. and Peyser, P. A. and Pirruccello, J. and Pollin, T. and Preuss, M. and Psaty, B. M. and Rao, D. C. and Redline, S. and Reed, R. and Reiner, A. and Rich, S. S. and Rosenthal, S. and Rotter, J. I. and Schoenberg, J. and Selvaraj, M. S. and Sheu, W. H. and Smith, J. A. and Sofer, T. and Stilp, A. M. and Sunyaev, S. R. and Surakka, I. and Sztalryd, C. and Tang, H. and Taylor, K. D. and Tsai, M. Y. and Uddin, M. M. and Urbut, S. and Verbanck, M. and Von Holle, A. and Wang, H. and Wang, F. F. and Wiggins, K. and Willer, C. J. and Wilson, J. G. and Wolford, B. and Xu, H. and Yanek, L. R. and Zaghloul, N. and Zekavat, M. and Zhang, J.} } @article {8987, title = {Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline.}, journal = {J Alzheimers Dis}, volume = {83}, year = {2021}, month = {2021}, pages = {1379-1389}, abstract = {

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95\%CI: 1.35,1.87); mid-life OR = 1.94 (95\%CI:1.16, 3.26); and late-life OR = 1.77 (95\%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95\%CI: 1.42,2.11) and late-life (OR = 1.43; 95\%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cognitive Dysfunction, Cohort Studies, Dementia, Depression, Female, Humans, Male, Middle Aged, Prodromal Symptoms, Risk Factors}, issn = {1875-8908}, doi = {10.3233/JAD-210588}, author = {Brenowitz, Willa D and Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Golden, Sherita H and Fitzpatrick, Annette L and Yaffe, Kristine} } @article {8774, title = {Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 06 09}, pages = {3505}, abstract = {

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1\% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60\% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

}, keywords = {Adult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment}, issn = {2041-1723}, doi = {10.1038/s41467-021-23556-4}, author = {Goodrich, Julia K and Singer-Berk, Moriel and Son, Rachel and Sveden, Abigail and Wood, Jordan and England, Eleina and Cole, Joanne B and Weisburd, Ben and Watts, Nick and Caulkins, Lizz and Dornbos, Peter and Koesterer, Ryan and Zappala, Zachary and Zhang, Haichen and Maloney, Kristin A and Dahl, Andy and Aguilar-Salinas, Carlos A and Atzmon, Gil and Barajas-Olmos, Francisco and Barzilai, Nir and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Centeno-Cruz, Federico and Chambers, John C and Chami, Nathalie and Chan, Edmund and Chan, Juliana and Cheng, Ching-Yu and Cho, Yoon Shin and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio and Correa, Adolfo and DeFronzo, Ralph A and Duggirala, Ravindranath and Dupuis, Jos{\'e}e and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Gieger, Christian and Glaser, Benjamin and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez, Ma Elena and Grarup, Niels and Groop, Leif and Gross, Myron and Haiman, Christopher and Han, Sohee and Hanis, Craig L and Hansen, Torben and Heard-Costa, Nancy L and Henderson, Brian E and Hernandez, Juan Manuel Malacara and Hwang, Mi Yeong and Islas-Andrade, Sergio and J{\o}rgensen, Marit E and Kang, Hyun Min and Kim, Bong-Jo and Kim, Young Jin and Koistinen, Heikki A and Kooner, Jaspal Singh and Kuusisto, Johanna and Kwak, Soo-Heon and Laakso, Markku and Lange, Leslie and Lee, Jong-Young and Lee, Juyoung and Lehman, Donna M and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lyssenko, Valeriya and Ma, Ronald C W and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Meigs, James B and Meitinger, Thomas and Mendoza-Caamal, Elvia and Mohlke, Karen L and Morris, Andrew D and Morrison, Alanna C and Ng, Maggie C Y and Nilsson, Peter M and O{\textquoteright}Donnell, Christopher J and Orozco, Lorena and Palmer, Colin N A and Park, Kyong Soo and Post, Wendy S and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Rotter, Jerome I and Saleheen, Danish and Schurmann, Claudia and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Spector, Timothy D and Strauch, Konstantin and Strom, Tim M and Tai, E Shyong and Tam, Claudia H T and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tracy, Russell P and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and van Dam, Rob M and Vasan, Ramachandran S and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Burtt, Noel P and Zaitlen, Noah and McCarthy, Mark I and Boehnke, Michael and Pollin, Toni I and Flannick, Jason and Mercader, Josep M and O{\textquoteright}Donnell-Luria, Anne and Baxter, Samantha and Florez, Jose C and MacArthur, Daniel G and Udler, Miriam S} } @article {8705, title = {Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 Apr 01}, pages = {564-582}, abstract = {

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5\%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained <=20 variants in the credible sets that jointly account for 99\% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.011}, author = {Graff, Mariaelisa and Justice, Anne E and Young, Kristin L and Marouli, Eirini and Zhang, Xinruo and Fine, Rebecca S and Lim, Elise and Buchanan, Victoria and Rand, Kristin and Feitosa, Mary F and Wojczynski, Mary K and Yanek, Lisa R and Shao, Yaming and Rohde, Rebecca and Adeyemo, Adebowale A and Aldrich, Melinda C and Allison, Matthew A and Ambrosone, Christine B and Ambs, Stefan and Amos, Christopher and Arnett, Donna K and Atwood, Larry and Bandera, Elisa V and Bartz, Traci and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Bielak, Lawrence F and Blot, William J and Bottinger, Erwin P and Bowden, Donald W and Bradfield, Jonathan P and Brody, Jennifer A and Broeckel, Ulrich and Burke, Gregory and Cade, Brian E and Cai, Qiuyin and Caporaso, Neil and Carlson, Chris and Carpten, John and Casey, Graham and Chanock, Stephen J and Chen, Guanjie and Chen, Minhui and Chen, Yii-der I and Chen, Wei-Min and Chesi, Alessandra and Chiang, Charleston W K and Chu, Lisa and Coetzee, Gerry A and Conti, David V and Cooper, Richard S and Cushman, Mary and Demerath, Ellen and Deming, Sandra L and Dimitrov, Latchezar and Ding, Jingzhong and Diver, W Ryan and Duan, Qing and Evans, Michele K and Falusi, Adeyinka G and Faul, Jessica D and Fornage, Myriam and Fox, Caroline and Freedman, Barry I and Garcia, Melissa and Gillanders, Elizabeth M and Goodman, Phyllis and Gottesman, Omri and Grant, Struan F A and Guo, Xiuqing and Hakonarson, Hakon and Haritunians, Talin and Harris, Tamara B and Harris, Curtis C and Henderson, Brian E and Hennis, Anselm and Hernandez, Dena G and Hirschhorn, Joel N and McNeill, Lorna Haughton and Howard, Timothy D and Howard, Barbara and Hsing, Ann W and Hsu, Yu-Han H and Hu, Jennifer J and Huff, Chad D and Huo, Dezheng and Ingles, Sue A and Irvin, Marguerite R and John, Esther M and Johnson, Karen C and Jordan, Joanne M and Kabagambe, Edmond K and Kang, Sun J and Kardia, Sharon L and Keating, Brendan J and Kittles, Rick A and Klein, Eric A and Kolb, Suzanne and Kolonel, Laurence N and Kooperberg, Charles and Kuller, Lewis and Kutlar, Abdullah and Lange, Leslie and Langefeld, Carl D and Le Marchand, Lo{\"\i}c and Leonard, Hampton and Lettre, Guillaume and Levin, Albert M and Li, Yun and Li, Jin and Liu, Yongmei and Liu, Youfang and Liu, Simin and Lohman, Kurt and Lotay, Vaneet and Lu, Yingchang and Maixner, William and Manson, JoAnn E and McKnight, Barbara and Meng, Yan and Monda, Keri L and Monroe, Kris and Moore, Jason H and Mosley, Thomas H and Mudgal, Poorva and Murphy, Adam B and Nadukuru, Rajiv and Nalls, Mike A and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Neslund-Dudas, Christine and Neuhouser, Marian L and Nyante, Sarah and Ochs-Balcom, Heather and Ogundiran, Temidayo O and Ogunniyi, Adesola and Ojengbede, Oladosu and Okut, Hayrettin and Olopade, Olufunmilayo I and Olshan, Andrew and Padhukasahasram, Badri and Palmer, Julie and Palmer, Cameron D and Palmer, Nicholette D and Papanicolaou, George and Patel, Sanjay R and Pettaway, Curtis A and Peyser, Patricia A and Press, Michael F and Rao, D C and Rasmussen-Torvik, Laura J and Redline, Susan and Reiner, Alex P and Rhie, Suhn K and Rodriguez-Gil, Jorge L and Rotimi, Charles N and Rotter, Jerome I and Ruiz-Narvaez, Edward A and Rybicki, Benjamin A and Salako, Babatunde and Sale, Mich{\`e}le M and Sanderson, Maureen and Schadt, Eric and Schreiner, Pamela J and Schurmann, Claudia and Schwartz, Ann G and Shriner, Daniel A and Signorello, Lisa B and Singleton, Andrew B and Siscovick, David S and Smith, Jennifer A and Smith, Shad and Speliotes, Elizabeth and Spitz, Margaret and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Sucheston, Lara and Sun, Yan V and Tajuddin, Salman M and Taylor, Herman and Taylor, Kira and Tayo, Bamidele O and Thun, Michael J and Tucker, Margaret A and Vaidya, Dhananjay and Van Den Berg, David J and Vedantam, Sailaja and Vitolins, Mara and Wang, Zhaoming and Ware, Erin B and Wassertheil-Smoller, Sylvia and Weir, David R and Wiencke, John K and Williams, Scott M and Williams, L Keoki and Wilson, James G and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yao, Jie and Zakai, Neil and Zanetti, Krista and Zemel, Babette S and Zhao, Wei and Zhao, Jing Hua and Zheng, Wei and Zhi, Degui and Zhou, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zmuda, Joe and Zonderman, Alan B and Psaty, Bruce M and Borecki, Ingrid B and Cupples, L Adrienne and Liu, Ching-Ti and Haiman, Christopher A and Loos, Ruth and Ng, Maggie C Y and North, Kari E} } @article {8976, title = {Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts.}, journal = {Circulation}, volume = {145}, year = {2022}, month = {2022 01 25}, pages = {268-278}, abstract = {

BACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established.

METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI>=30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes.

RESULTS: The study included 10 387 participants (52.9\% ARIC; 25.1\% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3\%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95\% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95\% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8\%, 29.9\%, and 13.7\%, respectively) versus those without diabetes (<=1\% for each).

CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.

}, keywords = {Aged, Cohort Studies, Diabetes Mellitus, Female, Heart Failure, Humans, Male, National Heart, Lung, and Blood Institute (U.S.), Obesity, Risk Factors, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.055830}, author = {Patel, Kershaw V and Segar, Matthew W and Lavie, Carl J and Kondamudi, Nitin and Neeland, Ian J and Almandoz, Jaime P and Martin, Corby K and Carbone, Salvatore and Butler, Javed and Powell-Wiley, Tiffany M and Pandey, Ambarish} } @article {9182, title = {Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {42}, year = {2022}, month = {2022 09}, pages = {e273-e288}, abstract = {

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

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

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

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

}, keywords = {Animals, Atherosclerosis, Cardiovascular Diseases, Carnitine, Humans, Meat, Methylamines, Risk Factors}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.121.316533}, author = {Wang, Meng and Wang, Zeneng and Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Fretts, Amanda and Sotoodehnia, Nona and Budoff, Matthew and DiDonato, Joseph A and McKnight, Barbara and Tang, W H Wilson and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9112, title = {Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 Jun 13}, pages = {580}, abstract = {

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

}, keywords = {Creatinine, Diabetes Mellitus, Diabetic Nephropathies, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney}, issn = {2399-3642}, doi = {10.1038/s42003-022-03448-z}, author = {Winkler, Thomas W and Rasheed, Humaira and Teumer, Alexander and Gorski, Mathias and Rowan, Bryce X and Stanzick, Kira J and Thomas, Laurent F and Tin, Adrienne and Hoppmann, Anselm and Chu, Audrey Y and Tayo, Bamidele and Thio, Chris H L and Cusi, Daniele and Chai, Jin-Fang and Sieber, Karsten B and Horn, Katrin and Li, Man and Scholz, Markus and Cocca, Massimiliano and Wuttke, Matthias and van der Most, Peter J and Yang, Qiong and Ghasemi, Sahar and Nutile, Teresa and Li, Yong and Pontali, Giulia and G{\"u}nther, Felix and Dehghan, Abbas and Correa, Adolfo and Parsa, Afshin and Feresin, Agnese and de Vries, Aiko P J and Zonderman, Alan B and Smith, Albert V and Oldehinkel, Albertine J and De Grandi, Alessandro and Rosenkranz, Alexander R and Franke, Andre and Teren, Andrej and Metspalu, Andres and Hicks, Andrew A and Morris, Andrew P and T{\"o}njes, Anke and Morgan, Anna and Podgornaia, Anna I and Peters, Annette and K{\"o}rner, Antje and Mahajan, Anubha and Campbell, Archie and Freedman, Barry I and Spedicati, Beatrice and Ponte, Belen and Sch{\"o}ttker, Ben and Brumpton, Ben and Banas, Bernhard and Kr{\"a}mer, Bernhard K and Jung, Bettina and {\r A}svold, Bj{\o}rn Olav and Smith, Blair H and Ning, Boting and Penninx, Brenda W J H and Vanderwerff, Brett R and Psaty, Bruce M and Kammerer, Candace M and Langefeld, Carl D and Hayward, Caroline and Spracklen, Cassandra N and Robinson-Cohen, Cassianne and Hartman, Catharina A and Lindgren, Cecilia M and Wang, Chaolong and Sabanayagam, Charumathi and Heng, Chew-Kiat and Lanzani, Chiara and Khor, Chiea-Chuen and Cheng, Ching-Yu and Fuchsberger, Christian and Gieger, Christian and Shaffer, Christian M and Schulz, Christina-Alexandra and Willer, Cristen J and Chasman, Daniel I and Gudbjartsson, Daniel F and Ruggiero, Daniela and Toniolo, Daniela and Czamara, Darina and Porteous, David J and Waterworth, Dawn M and Mascalzoni, Deborah and Mook-Kanamori, Dennis O and Reilly, Dermot F and Daw, E Warwick and Hofer, Edith and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Tai, E-Shyong and Catamo, Eulalia and Rizzi, Federica and Guo, Feng and Rivadeneira, Fernando and Guilianini, Franco and Sveinbjornsson, Gardar and Ehret, Georg and Waeber, G{\'e}rard and Biino, Ginevra and Girotto, Giorgia and Pistis, Giorgio and Nadkarni, Girish N and Delgado, Graciela E and Montgomery, Grant W and Snieder, Harold and Campbell, Harry and White, Harvey D and Gao, He and Stringham, Heather M and Schmidt, Helena and Li, Hengtong and Brenner, Hermann and Holm, Hilma and Kirsten, Holgen and Kramer, Holly and Rudan, Igor and Nolte, Ilja M and Tzoulaki, Ioanna and Olafsson, Isleifur and Martins, Jade and Cook, James P and Wilson, James F and Halbritter, Jan and Felix, Janine F and Divers, Jasmin and Kooner, Jaspal S and Lee, Jeannette Jen-Mai and O{\textquoteright}Connell, Jeffrey and Rotter, Jerome I and Liu, Jianjun and Xu, Jie and Thiery, Joachim and Arnl{\"o}v, Johan and Kuusisto, Johanna and Jakobsdottir, Johanna and Tremblay, Johanne and Chambers, John C and Whitfield, John B and Gaziano, John M and Marten, Jonathan and Coresh, Josef and Jonas, Jost B and Mychaleckyj, Josyf C and Christensen, Kaare and Eckardt, Kai-Uwe and Mohlke, Karen L and Endlich, Karlhans and Dittrich, Katalin and Ryan, Kathleen A and Rice, Kenneth M and Taylor, Kent D and Ho, Kevin and Nikus, Kjell and Matsuda, Koichi and Strauch, Konstantin and Miliku, Kozeta and Hveem, Kristian and Lind, Lars and Wallentin, Lars and Yerges-Armstrong, Laura M and Raffield, Laura M and Phillips, Lawrence S and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Lange, Leslie A and Citterio, Lorena and Klaric, Lucija and Ikram, M Arfan and Ising, Marcus and Kleber, Marcus E and Francescatto, Margherita and Concas, Maria Pina and Ciullo, Marina and Piratsu, Mario and Orho-Melander, Marju and Laakso, Markku and Loeffler, Markus and Perola, Markus and de Borst, Martin H and G{\"o}gele, Martin and Bianca, Martina La and Lukas, Mary Ann and Feitosa, Mary F and Biggs, Mary L and Wojczynski, Mary K and Kavousi, Maryam and Kanai, Masahiro and Akiyama, Masato and Yasuda, Masayuki and Nauck, Matthias and Waldenberger, Melanie and Chee, Miao-Li and Chee, Miao-Ling and Boehnke, Michael and Preuss, Michael H and Stumvoll, Michael and Province, Michael A and Evans, Michele K and O{\textquoteright}Donoghue, Michelle L and Kubo, Michiaki and K{\"a}h{\"o}nen, Mika and Kastarinen, Mika and Nalls, Mike A and Kuokkanen, Mikko and Ghanbari, Mohsen and Bochud, Murielle and Josyula, Navya Shilpa and Martin, Nicholas G and Tan, Nicholas Y Q and Palmer, Nicholette D and Pirastu, Nicola and Schupf, Nicole and Verweij, Niek and Hutri-K{\"a}h{\"o}nen, Nina and Mononen, Nina and Bansal, Nisha and Devuyst, Olivier and Melander, Olle and Raitakari, Olli T and Polasek, Ozren and Manunta, Paolo and Gasparini, Paolo and Mishra, Pashupati P and Sulem, Patrick and Magnusson, Patrik K E and Elliott, Paul and Ridker, Paul M and Hamet, Pavel and Svensson, Per O and Joshi, Peter K and Kovacs, Peter and Pramstaller, Peter P and Rossing, Peter and Vollenweider, Peter and van der Harst, Pim and Dorajoo, Rajkumar and Sim, Ralene Z H and Burkhardt, Ralph and Tao, Ran and Noordam, Raymond and M{\"a}gi, Reedik and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Rueedi, Rico and van Dam, Rob M and Carroll, Robert J and Gansevoort, Ron T and Loos, Ruth J F and Felicita, Sala Cinzia and Sedaghat, Sanaz and Padmanabhan, Sandosh and Freitag-Wolf, Sandra and Pendergrass, Sarah A and Graham, Sarah E and Gordon, Scott D and Hwang, Shih-Jen and Kerr, Shona M and Vaccargiu, Simona and Patil, Snehal B and Hallan, Stein and Bakker, Stephan J L and Lim, Su-Chi and Lucae, Susanne and Vogelezang, Suzanne and Bergmann, Sven and Corre, Tanguy and Ahluwalia, Tarunveer S and Lehtim{\"a}ki, Terho and Boutin, Thibaud S and Meitinger, Thomas and Wong, Tien-Yin and Bergler, Tobias and Rabelink, Ton J and Esko, T{\~o}nu and Haller, Toomas and Thorsteinsdottir, Unnur and V{\"o}lker, Uwe and Foo, Valencia Hui Xian and Salomaa, Veikko and Vitart, Veronique and Giedraitis, Vilmantas and Gudnason, Vilmundur and Jaddoe, Vincent W V and Huang, Wei and Zhang, Weihua and Wei, Wen Bin and Kiess, Wieland and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and G{\`a}o, Xin and Sim, Xueling and Wang, Ya Xing and Friedlander, Yechiel and Tham, Yih-Chung and Kamatani, Yoichiro and Okada, Yukinori and Milaneschi, Yuri and Yu, Zhi and Stark, Klaus J and Stefansson, Kari and B{\"o}ger, Carsten A and Hung, Adriana M and Kronenberg, Florian and K{\"o}ttgen, Anna and Pattaro, Cristian and Heid, Iris M} } @article {9111, title = {{DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {05}, pages = {2408}, abstract = {We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.}, author = {Wielscher, M. and Mandaviya, P. R. and Kuehnel, B. and Joehanes, R. and Mustafa, R. and Robinson, O. and Zhang, Y. and Bodinier, B. and Walton, E. and Mishra, P. P. and Schlosser, P. and Wilson, R. and Tsai, P. C. and Palaniswamy, S. and Marioni, R. E. and Fiorito, G. and Cugliari, G. and Karhunen, V. and Ghanbari, M. and Psaty, B. M. and Loh, M. and Bis, J. C. and Lehne, B. and Sotoodehnia, N. and Deary, I. J. and Chadeau-Hyam, M. and Brody, J. A. and Cardona, A. and Selvin, E. and Smith, A. K. and Miller, A. H. and Torres, M. A. and Marouli, E. and G{\`a}o, X. and van Meurs, J. B. J. and Graf-Schindler, J. and Rathmann, W. and Koenig, W. and Peters, A. and Weninger, W. and Farlik, M. and Zhang, T. and Chen, W. and Xia, Y. and Teumer, A. and Nauck, M. and Grabe, H. J. and Doerr, M. and Lehtim{\"a}ki, T. and Guan, W. and Milani, L. and Tanaka, T. and Fisher, K. and Waite, L. L. and Kasela, S. and Vineis, P. and Verweij, N. and van der Harst, P. and Iacoviello, L. and Sacerdote, C. and Panico, S. and Krogh, V. and Tumino, R. and Tzala, E. and Matullo, G. and Hurme, M. A. and Raitakari, O. T. and Colicino, E. and Baccarelli, A. A. and K{\"a}h{\"o}nen, M. and Herzig, K. H. and Li, S. and Conneely, K. N. and Kooner, J. S. and K{\"o}ttgen, A. and Heijmans, B. T. and Deloukas, P. and Relton, C. and Ong, K. K. and Bell, J. T. and Boerwinkle, E. and Elliott, P. and Brenner, H. and Beekman, M. and Levy, D. and Waldenberger, M. and Chambers, J. C. and Dehghan, A. and Jarvelin, M. R.} } @article {9259, title = {Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.}, journal = {Heart}, year = {2022}, month = {2022 Dec 22}, abstract = {

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.

METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.

RESULTS: The study included 1876 participants (age 77.7{\textpm}4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95\% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV{\textperiodcentered}ms, 95\% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.

CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2022-321633}, author = {Pellegrini, Cara N and B{\r u}zkov{\'a}, Petra and Oesterle, Adam and Heckbert, Susan R and Tracy, Russell P and Siscovick, David S and Mukamal, Kenneth J and Djouss{\'e}, Luc and Kizer, Jorge R} } @article {9582, title = {The determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study.}, journal = {Metabol Open}, volume = {20}, year = {2023}, month = {2023 Dec}, pages = {100261}, abstract = {

AIM: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults.

METHODS: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n~=~1924).

RESULTS: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels.

CONCLUSION: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

}, issn = {2589-9368}, doi = {10.1016/j.metop.2023.100261}, author = {Bene-Alhasan, Yakubu and Siscovick, David S and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {9588, title = {Determinants of mosaic chromosomal alteration fitness.}, journal = {medRxiv}, year = {2023}, month = {2023 Oct 21}, abstract = {

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

}, doi = {10.1101/2023.10.20.23297280}, author = {Pershad, Yash and Mack, Taralynn and Poisner, Hannah and Jakubek, Yasminka A and Stilp, Adrienne M and Mitchell, Braxton D and Lewis, Joshua P and Boerwinkle, Eric and Loos, Ruth J and Chami, Nathalie and Wang, Zhe and Barnes, Kathleen and Pankratz, Nathan and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Bis, Joshua C and Shojaie, Ali and Silverman, Edwin K and Cho, Michael H and Yun, Jeong and DeMeo, Dawn and Levy, Daniel and Johnson, Andrew and Mathias, Rasika and Taub, Margaret and Arnett, Donna and North, Kari and Raffield, Laura M and Carson, April and Doyle, Margaret F and Rich, Stephen S and Rotter, Jerome I and Guo, Xiuqing and Cox, Nancy and Roden, Dan M and Franceschini, Nora and Desai, Pinkal and Reiner, Alex and Auer, Paul L and Scheet, Paul and Jaiswal, Siddhartha and Weinstock, Joshua S and Bick, Alexander G} } @article {9745, title = {Development and validation of a machine learning-based approach to identify high-risk diabetic cardiomyopathy phenotype.}, journal = {Eur J Heart Fail}, year = {2024}, month = {2024 Sep 06}, abstract = {

AIMS: Abnormalities in specific echocardiographic parameters and cardiac biomarkers have been reported among individuals with diabetes. However, a comprehensive characterization of diabetic cardiomyopathy (DbCM), a subclinical stage of myocardial abnormalities that precede the development of clinical heart failure (HF), is lacking. In this study, we developed and validated a machine learning-based clustering approach to identify the high-risk DbCM phenotype based on echocardiographic and cardiac biomarker parameters.

METHODS AND RESULTS: Among individuals with diabetes from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of cardiovascular disease and other potential aetiologies of cardiomyopathy (training, n = 1199), unsupervised hierarchical clustering was performed using echocardiographic parameters and cardiac biomarkers of neurohormonal stress and chronic myocardial injury (total 25 variables). The high-risk DbCM phenotype was identified based on the incidence of HF on follow-up. A deep neural network (DeepNN) classifier was developed to predict DbCM in the ARIC training cohort and validated in an external community-based cohort (Cardiovascular Health Study [CHS]; n = 802) and an electronic health record (EHR) cohort (n = 5071). Clustering identified three phenogroups in the derivation cohort. Phenogroup-3 (n = 324, 27\% of the cohort) had significantly higher 5-year HF incidence than other phenogroups (12.1\% vs. 4.6\% [phenogroup 2] vs. 3.1\% [phenogroup 1]) and was identified as the high-risk DbCM phenotype. The key echocardiographic predictors of high-risk DbCM phenotype were higher NT-proBNP levels, increased left ventricular mass and left atrial size, and worse diastolic function. In the CHS and University of Texas (UT) Southwestern EHR validation cohorts, the DeepNN classifier identified 16\% and 29\% of participants with DbCM, respectively. Participants with (vs. without) high-risk DbCM phenotype in the external validation cohorts had a significantly higher incidence of HF (hazard ratio [95\% confidence interval] 1.61 [1.18-2.19] in CHS and 1.34 [1.08-1.65] in the UT Southwestern EHR cohort).

CONCLUSION: Machine learning-based techniques may identify 16\% to 29\% of individuals with diabetes as having a high-risk DbCM phenotype who may benefit from more aggressive implementation of HF preventive strategies.

}, issn = {1879-0844}, doi = {10.1002/ejhf.3443}, author = {Segar, Matthew W and Usman, Muhammad Shariq and Patel, Kershaw V and Khan, Muhammad Shahzeb and Butler, Javed and Manjunath, Lakshman and Lam, Carolyn S P and Verma, Subodh and Willett, DuWayne and Kao, David and Januzzi, James L and Pandey, Ambarish} } @article {9637, title = {Development and Validation of the American Heart Association{\textquoteright}s PREVENT Equations.}, journal = {Circulation}, volume = {149}, year = {2024}, month = {2024 Feb 06}, pages = {430-449}, abstract = {

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD.

METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets.

RESULTS: Among 6 612 004 adults included, mean{\textpm}SD age was 53{\textpm}12 years, and 56\% were women. Over a mean{\textpm}SD follow-up of 4.8{\textpm}3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; =0.01).

CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

}, keywords = {Adult, Aged, Albumins, American Heart Association, Atherosclerosis, Cardiovascular Diseases, Creatinine, Female, Glycated Hemoglobin, Heart Failure, Humans, Male, Middle Aged, Risk Assessment, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.123.067626}, author = {Khan, Sadiya S and Matsushita, Kunihiro and Sang, Yingying and Ballew, Shoshana H and Grams, Morgan E and Surapaneni, Aditya and Blaha, Michael J and Carson, April P and Chang, Alexander R and Ciemins, Elizabeth and Go, Alan S and Gutierrez, Orlando M and Hwang, Shih-Jen and Jassal, Simerjot K and Kovesdy, Csaba P and Lloyd-Jones, Donald M and Shlipak, Michael G and Palaniappan, Latha P and Sperling, Laurence and Virani, Salim S and Tuttle, Katherine and Neeland, Ian J and Chow, Sheryl L and Rangaswami, Janani and Pencina, Michael J and Ndumele, Chiadi E and Coresh, Josef} }