Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise.

Importance: Metabolic responses to exercise training are variable. Metabolite profiling may aid in the clinical assessment of an individual's responsiveness to exercise interventions. Objective: To investigate the association between a novel circulating biomarker of hepatic fat, dimethylguanidino valeric acid (DMGV), and metabolic health traits before and after 20 weeks of endurance exercise training. Design, Setting, and Participants: This study involved cross-sectional and longitudinal analyses of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997. White participants with sedentary lifestyles who were free of cardiometabolic disease were included. Metabolomic tests were performed using a liquid chromatography, tandem mass spectrometry method on plasma samples collected before and after exercise training in the HERITAGE study. Metabolomics and data analysis were performed from August 2017 to May 2018. Exposures: Plasma DMGV levels. Main Outcome and Measures: The association between DMGV levels and measures of body composition, plasma lipids, insulin, and glucose homeostasis before and after exercise training. Results: Among the 439 participants included in analyses from HERITAGE, the mean (SD) age was 36 (15) years, 228 (51.9%) were female, and the median (interquartile range) body mass index was 25 (22-28). Baseline levels of DMGV were positively associated with body fat percentage, abdominal visceral fat, very low-density lipoprotein cholesterol, and triglycerides, and inversely associated with insulin sensitivity, low-density lipoprotein cholesterol, high-density lipoprotein size, and high-density lipoprotein cholesterol (range of ß coefficients, 0.17-0.46 [SEs, 0.026-0.050]; all P < .001, after adjusting for age and sex). After adjusting for age, sex, and baseline traits, baseline DMGV levels were positively associated with changes in small high-density lipoprotein particles (ß, 0.14 [95% CI, 0.05-0.23]) and inversely associated with changes in medium and total high-density lipoprotein particles (ß, -0.15 [95% CI, -0.24 to -0.05] and -0.19 [95% CI, -0.28 to -0.10], respectively), apolipoprotein A1 (ß, -0.14 [95% CI, -0.23 to -0.05]), and insulin sensitivity (ß, -0.13; P = 3.0 × 10-3) after exercise training. Conclusions and Relevance: Dimethylguanidino valeric acid is an early marker of cardiometabolic dysfunction that is associated with attenuated improvements in lipid traits and insulin sensitivity after exercise training. Levels of DMGV may identify individuals who require additional therapies beyond guideline-directed exercise to improve their metabolic health.

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

LDL triglycerides, hepatic lipase activity, and coronary artery disease: An epidemiologic and Mendelian randomization study.

BACKGROUND AND AIMS: High concentrations of low density lipoprotein (LDL) triglycerides have been associated with prevalent angiographic coronary artery disease. The present analysis was designed to investigate the association of LDL triglycerides with cardiovascular mortality and to explore possible mechanisms that may link LDL triglycerides to cardiovascular risk. METHODS: LDL triglycerides were measured in 3140 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. They were prospectively followed for cardiovascular mortality (median duration 9.9 years). Genome wide association data for LDL triglycerides were available for 2900 LURIC participants. Genetic data and measurements of hepatic lipase activity were available for 478 participants of the HERITAGE Family study. Genome wide association data for cardiovascular disease were available for 184,305 participants of the CARDIoGRAMplusC4D consortium. RESULTS: There was a continuous positive association between LDL triglycerides and cardiovascular mortality (hazard ratio for 5th vs. 1st quintile = 2.53, p < 0.001) and this association was similar in males and females. Genome wide association analysis in LURIC revealed that LDL triglycerides were strongly associated with variation in the hepatic lipase region (p < 10-15 for rs1800588 and rs10468017). The LDL triglyceride raising alleles in rs1800588 and rs10468017 were associated with low hepatic lipase activity in HERITAGE and increased cardiovascular risk in CARDIoGRAMplusC4D. Two-sample Mendelian randomization analysis (HERITAGE and CARDIoGRAMplusC4D) using rs1800588 and rs10468017 as instrumental variable suggested that low hepatic lipase activity may cause increased cardiovascular risk (p = 0.013). CONCLUSIONS: Low hepatic lipase activity may link high LDL triglycerides to increased cardiovascular risk.

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Plasma Steroids are Not Associated with Resting and Exercise Blood Pressure.

We investigated the associations between steroid hormones and resting and exercise blood pressure in the sedentary state and in response to an exercise program controlling for sex, body mass, ethnicity, age, oral contraceptives, hormone therapy, smoking and alcohol intake in subjects from the HERITAGE Family Study.: In the sedentary state, 267 men (28% Blacks) and 301 women (37% Blacks) were available, and 241 men and 254 women completed the exercise program. Fourteen steroid hormones and sex hormone-binding globulin concentrations were assayed in a fasted state. Statistical significance was set at a Bonferroni adjusted p<0.0001. After controlling for the various covariates, only testosterone came close to a significant correlation with exercise systolic blood pressure at 50 W (r=-0.21, P=0.0006) in men. No other correlations with resting and exercise blood pressure traits were found at baseline. There were significant changes in blood pressure in response to the exercise program, but none of the correlations with baseline plasma steroids reached statistical significance. Plasma steroids do not correlate with resting and exercise blood pressure in sedentary adults and do not associate with blood pressure changes in response to a 20-week endurance exercise program.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Plasma steroids, body composition, and fat distribution: effects of age, sex, and exercise training.

BACKGROUND/OBJECTIVES: Plasma steroid hormone levels vary between men and women, but their associations with BMI and adiposity are controversial. Furthermore, little is known about the role of exercise programs on the relationship between steroid hormones and adiposity. This report evaluates these relationships for plasma levels of adrenal, gonadal, and conjugated steroids with body composition and fat distribution in sedentary men and women, aged 17-65 years, and their responses to an exercise program. SUBJECTS/METHODS: In the sedentary state, 270 men (29% Blacks) and 304 women (34% Blacks) from the HERITAGE Family Study were available. Among them, 242 men and 238 women completed a 20-week fully standardized exercise program. Fourteen steroid hormones and SHBG concentrations were assayed in a fasted state and were compared for their associations with adiposity in men and women and in response to the exercise program. Covariates adjusted for in partial correlation analysis were age, ancestry, menopause status (women), and oral contraceptives/hormone replacement treatment status (women) at baseline, as well as baseline value of the trait for the training response. Differences among normal weight, overweight, and obese subjects were also considered. Statistical significance was set at P < 0.0001. RESULTS: Baseline levels of dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone-binding globulin (SHBG), and testosterone (TESTO) were negatively associated with fat mass and abdominal fat (P < 0.0001) in men and for SHBG in women (P < 0.0001). TESTO was not correlated with fat-free mass in men or women, but was significantly associated with % fat-free mass in men. No association was detected between baseline steroid hormone levels and changes in adiposity traits in response to 20 weeks of exercise. CONCLUSION: In men, low DHT, OHPROG, SHBG, and TESTO were associated with higher adiposity and abdominal and visceral fat. A similar adiposity profile was observed in women with low SHBG.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Adropin: An endocrine link between the biological clock and cholesterol homeostasis.

OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. RESULTS: In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-ß-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. CONCLUSIONS: In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials.

OBJECTIVE:  To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials. DESIGN:  Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials. DATA SOURCES:  Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015. ELIGIBILITY CRITERIA FOR STUDY SELECTION:  Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity. RESULTS:  We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category. CONCLUSIONS:  We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions. SYSTEMATIC REVIEW REGISTRATION:  PROSPERO CRD42015015969.

An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

Advances in Exercise, Fitness, and Performance Genomics in 2015.

This review of the exercise genomics literature encompasses the highest-quality articles published in 2015 across seven broad topics: physical activity behavior, muscular strength and power, cardiorespiratory fitness and endurance performance, body weight and adiposity, insulin and glucose metabolism, lipid and lipoprotein metabolism, and hemodynamic traits. One study used a quantitative trait locus for wheel running in mice to identify single nucleotide polymorphisms (SNPs) in humans associated with physical activity levels. Two studies examined the association of candidate gene ACTN3 R577X genotype on muscular performance. Several studies examined gene-physical activity interactions on cardiometabolic traits. One study showed that physical inactivity exacerbated the body mass index (BMI)-increasing effect of an FTO SNP but only in individuals of European ancestry, whereas another showed that high-density lipoprotein cholesterol (HDL-C) SNPs from genome-wide association studies exerted a smaller effect in active individuals. Increased levels of moderate-to-vigorous-intensity physical activity were associated with higher Matsuda insulin sensitivity index in PPARG Ala12 carriers but not Pro12 homozygotes. One study combined genome-wide and transcriptome-wide profiling to identify genes and SNPs associated with the response of triglycerides (TG) to exercise training. The genome-wide association study results showed that four SNPs accounted for all of the heritability of △TG, whereas the baseline expression of 11 genes predicted 27% of △TG. A composite SNP score based on the top eight SNPs derived from the genomic and transcriptomic analyses was the strongest predictor of ΔTG, explaining 14% of the variance. The review concludes with a discussion of a conceptual framework defining some of the critical conditions for exercise genomics studies and highlights the importance of the recently launched National Institutes of Health Common Fund program titled "Molecular Transducers of Physical Activity in Humans."