Abstract Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
Metabolome captures complex states of metabolic homeostasis affected by genetic and environmental factors. A systematic understanding of metabolites associated with T2D risk may offer potentials for personalized risk monitoring and prevention. Here, we integrated data for 467 harmonized circulating metabolites, genetics, and diet/lifestyle factors in up to 23,616 racially diverse individuals from 10 cohorts with up to 26-y of follow-up. Through multivariable-adjusted metabolome-wide association analyses, we identified 235 metabolites associated with incident T2D (4,000 incident cases; FDR<0.05). Genetic determinants of these metabolites were mapped to genes implicated in pathways of nutrient/energy metabolism and glucose/lipid dysregulation (pathway enrichment FDR<0.05) and highly expressed in T2D-relevent tissues e.g., liver, adipose tissues, pancreas, and muscles (tissue-specific expression enrichment FDR<0.05). Mendelian randomization analyses further corroborated potential causal associations between 93 of the 235 metabolites and T2D. These included previously known (e.g., valine and isoleucine) and novel associations (e.g., α-ketoisocaproate in leucine metabolism, N-acetylaspartate in glutamate metabolism, and odd-chain fatty acid heptadecanoate). Furthermore, we analyzed metabolome-wide associations with 18 mutually adjusted modifiable risk factors. Several factors e.g., physical activity and whole grain (WG) intake, explained higher proportions of inter-individual variation of T2D-associated vs. other metabolites. We identified specific metabolites as potential mediators linking each risk factor to T2D (e.g., 4 metabolites mediated 22% of the WG-T2D association). In conclusion, we found known and novel metabolites associated with T2D risk, indicating potential biological pathways through which genetic and lifestyle factors contribute to T2D. Our findings may inform future personalized T2D prevention. Disclosure J.Li: None. J.Dupuis: None. E.Selvin: None. S.Bhupathiraju: None. J.A.Brody: None. Y.Liu: None. A.Eliassen: None. J.E.Manson: None. C.B.Clish: None. R.N.Lemaitre: None. K.L.Tucker: None. J.Hu: None. J.I.Rotter: None. M.A.Martinez-gonzalez: None. K.M.Rexrode: None. J.B.Meigs: Consultant; Quest Diagnostics. E.Boerwinkle: None. R.Kaplan: None. F.Hu: None. B.Yu: None. Q.Qi: None. N.The nhlbi topmed metabolomics and proteomics worki: n/a. L.Liang: None. M.Guasch: None. J.Merino: None. M.Ruiz-canela: None. K.Luo: None. C.Rebholz: None. B.Porneala: None. Funding National Institutes of Health (R00DK122128 to J.L.)
AimsHigh body mass index (BMI) is a risk factor for atrial fibrillation (AF). The aim of this study was to determine whether lean body mass (LBM) predicts AF.
Introduction: Chronic disruption of circadian rhythms is linked to weight gain and metabolic dysregulation. Time-restricted eating (TRE), a form of intermittent fasting, has shown effectiveness in improving short-term weight loss and energy homeostasis. However, associations between habitual adherence to TRE and long-term weight change remain understudied. Hypothesis: We tested whether adherence to TRE assessed by the gold-standard seven-day dietary records (7DDRs) was related to 5-year change in body weight among women. Methods: The present analysis included 650 women (mean [SD]: age 63 [9] y; BMI 26.4 [5.3] kg/m 2 ) without cardiovascular disease at baseline who completed 7DDRs in a sub-study of the Nurses’ Health Studies (NHS/NHSII), the Women’s Lifestyle Validation Study (WLVS) (2010-12). TRE was indicated by 4-12 hours of daily eating window (EW). The adherence to TRE was assessed by summing up the TRE days in a week. We also calculated 7-day averaged values of EW hours, last/first time of eating occasion (EO), and within-person variability of these variables. Weight change from baseline to a follow-up survey (NHS: 2016-18; NHSII: 2015-17) were analyzed. Total energy expenditure (TEE) and physical activity expenditure (PAEE) were measured at baseline using the doubly labeled water dilution method. Results: Longer averaged hours of EW were related to greater weight gain (β 0.7 [0.3] kg per 2 hours) after adjusting for covariates of demographic factors, total energy intake, physical activity, alcohol, within-person variation of EW, the averaged time of last EO, and the initial body weight ( p =0.02). Consistently, adherence to TRE was associated with less weight gain (β -0.25 [SE 0.1] kg per day increment; p =0.03) in a model adjusting for these covariates. We found that lower adherence to TRE and longer hours of EW were associated with weight gain ( p <0.05 for both) when the last eating time occurred at a later time in the day than at an earlier time. The baseline energy metabolism (TEE and PAEE) modified the associations between the hours of EW and weight changes ( P interaction-EW-TEE = 0.006; P interaction-EW-PAEE =0.01), showing significant relationships particularly among women with higher levels of adiposity and greater energy expenditure at baseline. Conclusions: Adherence to TRE and fewer habitual hours of eating were related to long-term weight changes among middle-aged and elderly women. The last eating time and energy homeostasis may partly modify the associations.
Vitamin D insufficiency is associated with risks of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited. To investigate the effects of vitamin D3 supplementation on CVD and cancer incidences. The study was a 5-year, randomized, placebo-controlled trial among 2495 male participants ≥60 years and post-menopausal female participants ≥65 years from a general Finnish population who were free of prior CVD or cancer. The study had 3 arms: placebo, 1600 IU/day, or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative subcohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers, and cancer death. During the follow-up, there were 41 (4.9%), 42 (5.0%), and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (compared with placebo: HR: 0.97; 95% CI: 0.63–1.49; P = 0.89), and 3200 IU/d (HR: 0.84; 95% CI: 0.54–1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%), and 40 (4.8%) participants in the placebo, 1600 IU/d (HR: 1.14; 95% CI: 0.75–1.72; P = 0.55), and 3200 IU/d (HR: 0.95; 95% CI: 0.61–1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the subcohort, the mean baseline serum 25-hydroxyvitamin D concentration was 75 nmol/L (SD, 18 nmol/L). After 12 months, the concentrations were 73 nmol/L (SD, 18 nmol/L), 100 nmol/L (SD, 21 nmol/L), and 120 nmol/L (SD, 22 nmol/L) in the placebo, 1600 IU/d, and 3200 IU/d arms, respectively. Vitamin D3 supplementation did not lower the incidences of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline.
