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Although sleep quality and duration have been related to cardiovascular end points, little is known about the association between sleep duration and incident atrial fibrillation (AF). Hence, we prospectively examined the association between sleep duration and incident AF in a cohort of 18,755 United States male physicians. Self-reported sleep duration was ascertained during a 2002 annual follow-up questionnaire. Incident AF was ascertained through annual follow-up questionnaires. Cox regression analysis was used to estimate the relative risks of AF. The average age at baseline was 67.7 ± 8.6 years. During a mean follow-up of 6.9 ± 2.1 years, 1,468 cases of AF occurred. Using 7 hours of sleep as the reference group, the multivariate adjusted hazard ratio for AF was 1.06 (95% confidence interval 0.92 to 1.22), 1.0 (reference), and 1.13 (95% confidence interval 1.00 to 1.27) from the lowest to greatest category of sleep duration (p for trend = 0.26), respectively. In a secondary analysis, no evidence was seen of effect modification by adiposity (p for interaction = 0.69); however, prevalent sleep apnea modified the relation of sleep duration with AF (p for interaction = 0.01). From the greatest to the lowest category of sleep duration, the multivariate-adjusted hazard ratio for AF was 2.26 (95% confidence interval 1.26 to 4.05), 1.0 (reference), and 1.34 (95% confidence interval 0.73 to 2.46) for those with prevalent sleep apnea and 1.01 (95% confidence interval 0.87 to 1.16), 1.0 (reference), and 1.12 (95% confidence interval 0.99 to 1.27) for those without sleep apnea, respectively. Our data showed a modestly elevated risk of AF with long sleep duration among United States male physicians. Furthermore, a shorter sleep duration was associated with a greater risk of AF in those with prevalent sleep apnea.

To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system. Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.

Although cross-sectional studies have identified lifestyle factors associated with high-density lipoprotein cholesterol (HDL-C), no studies have examined the association between changes in lifestyle factors and long-term changes in HDL-C. We examined the association between changes in lifestyle factors and changes in HDL-C over a 14-year period in a cohort of 4,168 US male physicians, followed up between 1982 and 1997 and with HDL-C measured at both time points. Using linear regression, we examined the association between HDL-C change and categorized changes in alcohol consumption, physical activity, body mass index (BMI), and smoking, adjusting for age, baseline HDL-C, and other covariates. Stable BMI of <25 kg/m2 or BMI reduction from ≥25 to <25 kg/m2 were associated with increases in HDL-C of 3.1 to 4.7 mg/dL over 14 years. Alcohol consumption of ≥1 drink daily or increase in alcohol consumption from <1 to ≥1 drink daily was associated with increases in HDL-C of 2.4 to 3.3 mg/dL over 14 years. Adopting a sedentary lifestyle was associated with decreases in 14-year decreases in HDL-C. These findings suggest that reductions in BMI and increases in alcohol consumption are associated with 14-year increases in HDL-C, whereas decreases in physical activity are associated with 14-year decreases in HDL-C.

Background The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts ( N -range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). Results Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen’s d  < 0.259, p  < 7.80 × 10 −4 ). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p  < 0.05) confounding in the GWAS statistics. Conclusions This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

BackgroundA healthful plant-based diet was associated with lower risks of coronary heart disease and type 2 diabetes, and a favourable profile of adiposity-associated biomarkers, while an unhealthful plant-based diet was associated with elevated risk of cardiometabolic disease in health professional populations. However, little is known about the associations between plant-based dietary patterns and risk of cardiovascular disease (CVD) in US veterans.MethodsThe study population consisted of 148 506 participants who were free of diabetes, CVD and cancer at baseline in the Veterans Affairs (VA) Million Veteran Program. Diet was assessed using a Food Frequency Questionnaire at baseline. We calculated an overall Plant-Based Diet Index (PDI), a healthful PDI (hPDI) and an unhealthful PDI (uPDI). The CVD endpoints included non-fatal myocardial infarction (MI) and acute ischaemic stroke (AIS) identified through high-throughput phenotyping algorithms approach and fatal CVD events identified by searching the National Death Index.ResultsWith up to 8 years of follow-up, we documented 5025 CVD cases. After adjustment for confounding factors, a higher PDI was significantly associated with a lower risk of CVD (HR comparing extreme quintiles=0.75, 95% CI 0.68 to 0.82, P trend<0.0001). We observed an inverse association between hPDI and the risk of CVD (HR comparing extreme quintiles=0.71, 95% CI 0.64 to 0.78, P trend<0.001), whereas uPDI was positively associated with the risk of CVD (HR comparing extreme quintiles=1.12, 95% CI 1.02 to 1.24, P trend<0.001). We found similar associations of hPDI with subtypes of CVD; a 10-unit increment in hPDI was associated with HRs (95% CI) of 0.81 (0.75 to 0.87) for fatal CVD, 0.86 (0.79 to 0.94) for non-fatal MI and 0.86 (0.78 to 0.95) for non-fatal AIS.ConclusionsPlant-based dietary pattern enriched with healthier plant foods was associated with a substantially lower CVD risk in US veterans.

Previous studies have suggested that vitamin D deficiency might contribute to the pathogenesis of heart failure (HF); however, limited data are available on the association of vitamin D-binding protein (VDBP)—a major transport protein for vitamin D—and the development of HF. Thus, we investigated whether plasma VDBP is inversely associated with HF risk. Using a prospective nested case-control design, we selected 464 cases and 464 matched controls from the Physicians' Health Study for the present analyses. VDBP was determined using an enzyme-linked immunoassay. Self-reported HF was obtained through annual follow-up questionnaires and validated in a subsample by a review of the medical records. We used conditional logistic regression analyses to compute the adjusted odds ratios. The mean age was 58.6 years, and the median VDBP was 307.8 μg/ml (interquartile range 265.2 to 354.6). Plasma VDBP was not associated with HF in our study. Across the consecutive quintiles of VDBP, the odds ratio was 1.0 (95% confidence interval [CI] reference), 1.05 (95% CI 0.66 to 1.65), 1.28 (95% CI 0.80 to 2.06), 1.07 (95% CI 0.65 to 1.75), and 1.28 (95% CI 0.76 to 2.15); p for linear trend = 0.41, after adjustment for matching factors, body mass index, diabetes, atrial fibrillation, hypertension, and high-sensitivity C-reactive protein. In conclusion, our data have shown no significant association between the plasma levels of VDBP and HF risk in apparently healthy male physicians.

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

Elevated plasma levels of branched chain amino acids detected prior to pancreatic cancer diagnosis may result from whole body tissue breakdown occurring during the early stages of this disease. Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months 1 . PDAC has been linked with obesity and glucose intolerance 2 , 3 , 4 , but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras -driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven ( CAMK2D , PRKD1 , PRKD3 , MAPK3 , TNFSF12 , APOC3 and NAE1 ) proteins as potential targets for interventions to be used in primary prevention of heart failure. Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.