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1.
JAMA Cardiol ; 4(7): 636-643, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166569

RESUMO

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.

2.
Hum Mol Genet ; 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-31127295

RESUMO

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.

3.
Nat Genet ; 51(4): 636-648, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926973

RESUMO

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.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Fumar/sangue , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estilo de Vida , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Atherosclerosis ; 282: 37-44, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685440

RESUMO

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.

5.
Am J Epidemiol ; 188(6): 1033-1054, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698716

RESUMO

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.

6.
Int J Sports Med ; 39(13): 967-971, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30290373

RESUMO

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.

7.
Mol Psychiatry ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988085

RESUMO

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.

8.
PLoS One ; 13(6): e0198166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29912962

RESUMO

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.

9.
Int J Obes (Lond) ; 42(7): 1366-1377, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29507393

RESUMO

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.

10.
Am J Hum Genet ; 102(3): 375-400, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29455858

RESUMO

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).

11.
Mol Metab ; 8: 51-64, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29331507

RESUMO

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.

12.
BMJ ; 354: i4707, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27650503

RESUMO

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.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Obesidade/dietoterapia , Obesidade/genética , Perda de Peso/genética , Adiposidade/genética , Alelos , Predisposição Genética para Doença , Genótipo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Med Sci Sports Exerc ; 48(10): 1906-16, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27183119

RESUMO

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."


Assuntos
Exercício/fisiologia , Genômica , Aptidão Física/fisiologia , Adiposidade , Glicemia/metabolismo , Peso Corporal , Aptidão Cardiorrespiratória/fisiologia , Comportamentos Relacionados com a Saúde/fisiologia , Hemodinâmica/fisiologia , Humanos , Insulina/sangue , Metabolismo dos Lipídeos , Força Muscular/fisiologia , Resistência Física/fisiologia
14.
Genet Epidemiol ; 40(5): 404-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27230302

RESUMO

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.


Assuntos
Pressão Sanguínea/genética , Interação Gene-Ambiente , Fumar , Estudos de Coortes , Bases de Dados Factuais , Família , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
15.
PLoS One ; 11(1): e0147330, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26824906

RESUMO

There are strong genetic components to cardiorespiratory fitness and its response to exercise training. It would be useful to understand the differences in the genomic profile of highly trained endurance athletes of world class caliber and sedentary controls. An international consortium (GAMES) was established in order to compare elite endurance athletes and ethnicity-matched controls in a case-control study design. Genome-wide association studies were undertaken on two cohorts of elite endurance athletes and controls (GENATHLETE and Japanese endurance runners), from which a panel of 45 promising markers was identified. These markers were tested for replication in seven additional cohorts of endurance athletes and controls: from Australia, Ethiopia, Japan, Kenya, Poland, Russia and Spain. The study is based on a total of 1520 endurance athletes (835 who took part in endurance events in World Championships and/or Olympic Games) and 2760 controls. We hypothesized that world-class athletes are likely to be characterized by an even higher concentration of endurance performance alleles and we performed separate analyses on this subsample. The meta-analysis of all available studies revealed one statistically significant marker (rs558129 at GALNTL6 locus, p = 0.0002), even after correcting for multiple testing. As shown by the low heterogeneity index (I2 = 0), all eight cohorts showed the same direction of association with rs558129, even though p-values varied across the individual studies. In summary, this study did not identify a panel of genomic variants common to these elite endurance athlete groups. Since GAMES was underpowered to identify alleles with small effect sizes, some of the suggestive leads identified should be explored in expanded comparisons of world-class endurance athletes and sedentary controls and in tightly controlled exercise training studies. Such studies have the potential to illuminate the biology not only of world class endurance performance but also of compromised cardiac functions and cardiometabolic diseases.


Assuntos
Atletas , Heterogeneidade Genética , Genoma Humano , Resistência Física/genética , Adulto , Alelos , Variações do Número de Cópias de DNA , Expressão Gênica , Frequência do Gene , Loci Gênicos , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fluxo Expiratório Máximo/genética , N-Acetilgalactosaminiltransferases/genética , Consumo de Oxigênio/genética , Aptidão Física , Polimorfismo de Nucleotídeo Único , Comportamento Sedentário
16.
Atherosclerosis ; 243(2): 364-72, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26520888

RESUMO

OBJECTIVE: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. METHODS: Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. RESULTS: Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value. CONCLUSIONS: Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise-induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk.


Assuntos
Exercício , Estilo de Vida , Lipoproteínas/sangue , Lipoproteínas/classificação , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Grupos de Populações Continentais , Feminino , Nível de Saúde , Lipoproteínas de Alta Densidade Pré-beta/sangue , Lipoproteínas de Alta Densidade Pré-beta/classificação , Humanos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/classificação , Lipoproteínas VLDL/sangue , Lipoproteínas VLDL/classificação , Masculino , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Tamanho da Partícula , Fatores Sexuais , Adulto Jovem
17.
Med Sci Sports Exerc ; 47(6): 1105-12, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25706296

RESUMO

This is the annual review of the exercise genomics literature in which we report on the highest quality papers published in 2014. We identified a number of noteworthy papers across a number of fields. In 70-89 yr olds, only 19% of angiotensin-converting enzyme (ACE) II homozygotes exhibited significant improvement in gait speed in response to a yearlong physical activity program compared to 30% of ACE D-allele carriers. New studies continue to support the notion that the genetic susceptibility to obesity, as evidenced by a genomic risk score (GRS; based on multiple single nucleotide polymorphisms), is attenuated by 40%-50% in individuals who are physically active, compared to those who are sedentary. One study reported that the polygenic risk for hypertriglyceridemia was reduced by 30%-40% in individuals with high cardiorespiratory fitness. One report showed that there was a significant interaction of a type 2 diabetes GRS with physical activity, with active individuals having the lowest risk of developing diabetes. The protective effect of physical activity was most pronounced in the low GRS tertile (hazard ratio, 0.82). The interaction observed with the diabetes GRS seemed to be dependent on a genetic susceptibility to insulin resistance and not insulin secretion. A significant interaction between PPARα sequence variants and physical activity levels on cardiometabolic risk was observed, with higher activity levels associated with lower risk only in carriers of specific genotypes and haplotypes. The review concludes with a discussion of the importance of replication studies when very large population or intervention discovery studies are not feasible or are cost prohibitive.


Assuntos
Desempenho Atlético/fisiologia , Exercício/fisiologia , Genômica/tendências , Aptidão Física/fisiologia , Adiposidade/genética , Animais , Predisposição Genética para Doença , Genótipo , Hemodinâmica/genética , Humanos , Insulina/genética , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Força Muscular/genética , Fenótipo , Resistência Física/genética
18.
Circ Res ; 116(5): 909-22, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25722444

RESUMO

Clustering of obesity, coronary artery disease, and cardiovascular disease risk factors is observed in epidemiological studies and clinical settings. Twin and family studies have provided some supporting evidence for the clustering hypothesis. Loci nearest a lead single nucleotide polymorphism (SNP) showing genome-wide significant associations with coronary artery disease, body mass index, C-reactive protein, blood pressure, lipids, and type 2 diabetes mellitus were selected for pathway and network analyses. Eighty-seven autosomal regions (181 SNPs), mapping to 56 genes, were found to be pleiotropic. Most pleiotropic regions contained genes associated with coronary artery disease and plasma lipids, whereas some exhibited coaggregation between obesity and cardiovascular disease risk factors. We observed enrichment for liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor/RXR nuclear receptor signaling among pleiotropic genes and for signatures of coronary artery disease and hepatic steatosis. In the search for functionally interacting networks, we found that 43 pleiotropic genes were interacting in a network with an additional 24 linker genes. ENCODE (Encyclopedia of DNA Elements) data were queried for distribution of pleiotropic SNPs among regulatory elements and coding sequence variations. Of the 181 SNPs, 136 were annotated to ≥ 1 regulatory feature. An enrichment analysis found over-representation of enhancers and DNAse hypersensitive regions when compared against all SNPs of the 1000 Genomes pilot project. In summary, there are genomic regions exerting pleiotropic effects on cardiovascular disease risk factors, although only a few included obesity. Further studies are needed to resolve the clustering in terms of DNA variants, genes, pathways, and actionable targets.


Assuntos
Doenças Cardiovasculares/genética , Redes Reguladoras de Genes , Obesidade/genética , Doenças Cardiovasculares/epidemiologia , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Países Desenvolvidos , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Dislipidemias/epidemiologia , Dislipidemias/genética , Elementos Facilitadores Genéticos , Epistasia Genética , Feminino , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Herança Multifatorial , Obesidade/epidemiologia , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Fatores de Risco , Comportamento Sedentário , Distribuição por Sexo , Fumar/epidemiologia , Resultado do Tratamento , Estudos em Gêmeos como Assunto
19.
Hum Mol Genet ; 23(17): 4569-80, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24722204

RESUMO

MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA-target interaction can simultaneously affect multiple other miRNA-target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3'-untranslated region (3'UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.


Assuntos
Ansiedade/genética , Hipertensão/genética , MicroRNAs/metabolismo , Acetilcolinesterase/genética , Alelos , Animais , Sequência de Bases , Pressão Sanguínea , Encéfalo/metabolismo , Feminino , Predisposição Genética para Doença , Voluntários Saudáveis , Heterozigoto , Homozigoto , Humanos , Hidrocortisona/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Interleucina-6/genética , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Primatas/genética , Especificidade da Espécie , Proteína cdc42 de Ligação ao GTP/metabolismo
20.
Med Sci Sports Exerc ; 46(5): 851-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24743105

RESUMO

The most significant and scientifically sound articles in exercise genomics that were published in 2013 are reviewed in this report. No article on the genetic basis of sedentary behavior or physical activity level was identified. A calcineurin- and alpha actinin-2-based mechanism has been identified as the potential molecular basis for the observed lower muscular strength and power in alpha actinin-3-deficient individuals. Although baseline muscle transcriptomic signatures were found to be associated with strength training-induced muscle hypertrophy, no predictive genomic variants could be identified as of yet. One study found no clear evidence that the inverse relation between physical activity level and incident CHD events was influenced by 58 genomic variants clustered into four genetic scores. Lower physical activity level in North American populations may be driving the apparent risk of obesity in fat mass- and obesity-associated gene (FTO)-susceptible individuals compared with more active populations. Two large studies revealed that common genetic variants associated with baseline levels of plasma HDL cholesterol and triglycerides are not clear predictors of changes induced by interventions focused on weight loss, diet, and physical activity behavior. One large study from Japan reported that a higher fitness level attenuated the arterial stiffness-promoting effect of the Ala54 allele at the fatty acid binding protein 2 locus, which is a controversial finding because previous studies have suggested that Thr54 was the risk allele. Using transcriptomics to generate genomic targets in an unbiased manner for subsequent DNA sequence variants studies appears to be a growing trend. Moreover, exercise genomics is rapidly embracing gene and pathway analysis to better define the underlying biology and provide a foundation for the study of human variation.


Assuntos
Exercício/fisiologia , Genômica , Aptidão Física/fisiologia , Adiposidade , Glicemia/metabolismo , Peso Corporal , Fenômenos Fisiológicos Cardiovasculares , Hemodinâmica , Humanos , Insulina/sangue , Lipídeos/sangue , Lipoproteínas/sangue , Força Muscular/fisiologia , Resistência Física/fisiologia , Treinamento de Resistência , Respiração
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