Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, ...and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O(2) uptake (VO(2max)) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genome-wide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in VO(2max) Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 × 10(-4). Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in VO(2max) trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their VO(2max) by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ~6% of the training response of VO(2max). The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDM1); glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A); K(+) channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ~68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in VO(2max) in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of Vo(2max) to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted.
Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed.
An adverse ...response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors.
Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.
Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of ...sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ~580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4 × 10(-30)). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6 × 10(-13)) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = -2.3; P = 3 × 10(-7))) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent "generic" physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18-78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ~500 genes highly enriched in post-transcriptional processes (P = 1 × 10(-6)) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01-0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.
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.
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.
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).
Low hepatic lipase activity may link high LDL triglycerides to increased cardiovascular risk.
•High LDL triglycerides are associated with increased cardiovascular mortality, both in males and females.•LDL triglycerides are strongly associated with variants in the hepatic lipase region, both in males and females.•Low hepatic lipase acitivity implicates high LDL triglycerides.•Low hepatic lipase activity appears to be a causal cardiovascular risk factor.
The Human Obesity Gene Map: The 2005 Update Rankinen, Tuomo; Zuberi, Aamir; Chagnon, Yvon C. ...
Obesity (Silver Spring, Md.),
April 2006, Volume:
14, Issue:
4
Journal Article
Peer reviewed
This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single‐gene mutation obesity cases, Mendelian ...disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross‐breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single‐gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity‐related phenotypes from 61 genome‐wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http:obesitygene.pbrc.edu
The molecular pathways that are activated and contribute to physiological remodeling of skeletal muscle in response to endurance exercise have not been fully characterized. We previously reported ...that ∼800 gene transcripts are regulated following 6 wk of supervised endurance training in young sedentary males, referred to as the training-responsive transcriptome (TRT) (Timmons JA et al. J Appl Physiol 108: 1487-1496, 2010). Here we utilized this database together with data on biological variation in muscle adaptation to aerobic endurance training in both humans and a novel out-bred rodent model to study the potential regulatory molecules that coordinate this complex network of genes. We identified three DNA sequences representing RUNX1, SOX9, and PAX3 transcription factor binding sites as overrepresented in the TRT. In turn, miRNA profiling indicated that several miRNAs targeting RUNX1, SOX9, and PAX3 were downregulated by endurance training. The TRT was then examined by contrasting subjects who demonstrated the least vs. the greatest improvement in aerobic capacity (low vs. high responders), and at least 100 of the 800 TRT genes were differentially regulated, thus suggesting regulation of these genes may be important for improving aerobic capacity. In high responders, proangiogenic and tissue developmental networks emerged as key candidates for coordinating tissue aerobic adaptation. Beyond RNA-level validation there were several DNA variants that associated with maximal aerobic capacity (Vo(₂max)) trainability in the HERITAGE Family Study but these did not pass conservative Bonferroni adjustment. In addition, in a rat model selected across 10 generations for high aerobic training responsiveness, we found that both the TRT and a homologous subset of the human high responder genes were regulated to a greater degree in high responder rodent skeletal muscle. This analysis provides a comprehensive map of the transcriptomic features important for aerobic exercise-induced improvements in maximal oxygen consumption.
Physical activity level is an important component of the total daily energy expenditure and as such contributes to body weight regulation. A body of data indicates that the level of physical activity ...plays a role in the risk of excessive weight gain, in weight loss programs, and particularly in the prevention of weight regain. Most studies dealing with potential gene–physical activity interaction effects use an exercise and fitness or performance paradigm as opposed to an obesity‐driven model. From these studies, it is clear that there are considerable individual differences in the response to an exercise regimen and that there is a substantial familial aggregation component to the observed heterogeneity. Few studies have focused on the role of specific genes in accounting for the highly prevalent gene–exercise interaction effects. Results for specific genes have been inconsistent with few exceptions. Progress is likely to come when studies will be designed to truly address gene–exercise or physical activity interaction issues and with sample sizes that will provide adequate statistical power.
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."
Abstract 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.
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