Publications

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.

No abstract is provided for this article.

No abstract is provided for this article.

Introduction: Although exercise training is known to alter body composition, the molecular biomarkers and mechanisms related to these changes have not been fully elucidated. The purpose of this study was to examine the associations between plasma proteins and body composition traits before and after exercise training. Methods: Measurements were taken before and after 20 weeks of standardized, endurance training in self-identified Black and White adults of the HERITAGE Family Study (n=647). Plasma proteins were measured using an affinity-based platform (n=4979 aptamers). 11 body composition traits were measured using underwater weighing, CT scans, and anthropometry: BMI, body surface area, fat mass, fat free mass, %fat, waist circumference, waist-to-hip ratio, body weight, and abdominal visceral, subcutaneous, and total fat. Linear mixed models were used to test the association between plasma proteins and each trait at baseline and in response to training with full covariate adjustment ( Table 1 ). Significance was set to FDR<0.05. Results: On average, subjects were [mean and (SD)] 35 (14) years old, 33% Black, 54% female, and had BMI 26.2 (5.2) kg/m 2 . The number of significant associations between proteins and traits at baseline and in response to exercise training ranged from 645-1714 and 0-42, respectively ( Table 1 ). While leptin was among the top associated proteins at both time points for almost all traits, our analysis revealed many novel associations between changes in proteins with changes in body composition. Changes in DLK-1 significantly associated with changes in 9 of 11 traits but was not associated with baseline measures. Conclusions: Numerous plasma proteins were associated with body composition traits at baseline, with fewer associated with trait responses to training. Notably, we identified a subset of proteins uniquely associated with exercise-induced changes in body composition traits.

No abstract is provided for this article.

543 The chronic effects of exercise on ratings of perceived exertion (RPE), systolic blood pressure (SBP), heart rate (HR) and rate-pressure product (RPP) at the ventilatory threshold (VT) were investigated in 442 sedentary Caucasian and African-American men (n=228, age range=17-65, mean=35.1±13.9, ±SD) and women (n=214, age range=17-65, mean=32.5±12.1, ±SD) in the HERITAGE Family Study (HERITAGE). Cycle ergometer training was performed and monitored in the lab three times a week for 20 weeks starting at 55% VO2max and ending at 75% VO2max. VT was determined using standardized ventilatory methods pre- and post-training and RPE, HR and SBP were interpolated at VT from incremental measurements. RPE, HR, SBP and RPP at pre-training VT workload decreased significantly post-training (−2.7±0.15 [−25%] Borg '6-20' units, −15.4±0.96 [−12%] beats/min, −11.1±0.84 [−7%] mmHg, −3826±12.7 [−18%]HR × SBP respectively, p<.0001, ±SE). No significant post-training reductions in resting HR, SBP or RPP were found. Pre-training VO2 at VT (17.7±4.3 ml/kg/min≈5METS) was similar to that reported for common activities of daily living (ADL). These data show that HERITAGE training reduced participants' RPE, SBP, HR and RPP for intensities of physical activities required by ADL. Thus, HERITAGE participants should be able post-training to perform ADL with less perceived effort, a lower HR, lower SBP and reduced myocardial O2 requirements as estimated by the RPP. Supported by NHLBI HL47317 and NIH MO1-RR000400.

Sedentary behavior, usually quantified as sitting time, has been shown to be associated with several adverse health outcomes, even among individuals who meet the current recommendations for physical activity. Both twin and family studies have shown that sedentary behavior aggregates in families and is a heritable trait. However, little is known about genes and DNA sequence variants that contribute to propensity to be sedentary. The purpose of our study was to conduct a genome-wide association study to identify genomic regions and DNA sequence variants associated with sedentary time. A total of 67,530 Caucasians (56% female, mean age 62.1 years [SD 12.5]) from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) cohort were used for the discovery analyses. Other RPGEH ethnicities (African-Americans: N=2,500; East Asians: N=6,300; Hispanics: N=8,800) were used for replication studies. Information on daily sitting time outside of work was obtained by a questionnaire. A custom panel of 657,184 autosomal single nucleotide polymorphisms (SNPs) was genotyped using Affymetrix platform. Associations between sedentary time (dichotomized; cases 3 hours or more, controls less than 3 hours per day) and the SNPs were tested with PLINK logistic model using age, sex, BMI and admixture principal components as covariates. The strongest evidence of association was detected on chromosome 8p23.1. A total of 24 SNPs within a 1.34 Mb region were associated with sedentary time at genome-wide significance level (p&lt;5x10 -8 ), with SNP rs11774552 showing the peak association (OR=0.924, p= 1.7x10 -12 ). Sex-specific analyses confirmed that the associations were present both in men and women. The same SNPs were not associated with sedentary time in other ethnicities. However, SNP rs28754712, which is located in the immediate vicinity (+456 bp) of rs11774552, showed a significant association with sedentary time (OR=0.795, p=1.2x10 -3 ) in African-Americans. In summary, our results provide the first evidence of genomic region and DNA sequence variants associated with sedentary behavior in humans. If confirmed in additional replication studies, these findings will advance our understanding of biological mechanisms contributing to propensity to be sedentary.

A simple model of familial aggregation was applied to age-sex corrected systolic (SBP) and diastolic (DBP) blood pressure data from two separate studies: The Québec Family Study and the Tecumseh Community Health Study. Examination of the familial correlations suggested heterogeneity across studies in all DBP correlations, but for SBP only spouse correlations were higher in Québec. Fitting the path model to the data revealed that the only source of heterogeneity for SBP was in spouse resemblance (u), which was significant in Québec but could be dropped from the model in Tecumseh. For SBP, no further heterogeneity was detected, with the vertical transmission being compatible with (but not evidence for) purely polygenic inheritance (i.e., τf = τm = 1/2). Familiality estimates (t2 ) for SBP were quite high (nearly 40%), and extra sibling resemblance was significant. For DBP, heterogeneity was detected in all parameters of the model except for spouse resemblance. Common sibship environmental effects (b) were of little importance in Tecumseh but were highly significant in Québec. Vertical transmission from mothers (τm ) could be fixed at 1/2 in Tecumseh but was only about half as large in Québec, and familiality estimates were higher in Québec (nearly 60%) than in Tecumseh (about 25%). One source of the heterogeneity for SBP was due to cohabitation, which positively impacted on sibling correlations. The source of the sample heterogeneity in DBP may be through environmental factors which have a smaller impact in Tecumseh than in Québec, although genetic heterogeneity could not be ruled out. Differences in the study designs, as well as differences in the two populations, could account for the heterogeneity detected.

Thériault, G.; Diano, R.; Leblanc, C.; Perusse, L.; Landry, F. FACSH; Bouchard, C. FACSM. Author Information

We investigated whether the Arg16Gly and Gln27Glu polymorphisms of the β2‐adrenergic receptor gene were associated with body‐fat and fat‐distribution phenotypes measured before and in response to a 20‐week endurance‐training program. BMI, fat mass (FAT), percentage of body fat (%FAT), sum of eight skinfolds (SF8), and abdominal fat areas assessed by computed tomography were measured in adult sedentary white and black participants of the HERITAGE Family Study. Evidence of gene‐by‐obesity interaction was found in whites for several adiposity phenotypes measured before training. Analyses performed separately in nonobese and obese subjects revealed that obese men carrying the Glu27 allele have lower fat accumulation (BMI, FAT, and %FAT) than noncarriers. Among white obese women, Gly16Gly homozygotes had a lower fat accumulation (BMI, FAT, and SF8) than Arg16Gly and Arg16Arg carriers. In response to endurance training, white women with the Arg16Arg genotype exhibited a greater reduction in BMI, FAT, and %FAT. Results observed in blacks were mostly negative. These results suggest that polymorphisms in the β2‐adrenergic receptor gene influence the amount of body fat in white obese men (Gln27Glu) and women (Arg16Gly), as well as the changes in adiposity in response to endurance training in white women (Arg16Gly).

Introduction: Angiopoietin like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of lipoprotein lipase and modifiable by regular exercise. However, the molecular biomarkers related to their exercise responses have not been fully elucidated. The purpose of this study was to examine the associations between plasma proteins and ANGPTL3/8 and 4/8 before and after exercise training. Methods: Measurements were taken before and after 20 weeks of exercise training in 630 adults (36% Black, 56% women, mean age 35 yrs) of the HERITAGE Family Study. Meso Scale Discovery immunoassays were used to measure ANGPTL3/8 and ANGPTL4/8 complexes in serum. Plasma proteins (n=4979 aptamers) were quantified using SomaScan. Linear mixed models tested the association between plasma proteins and each trait at baseline and post- training with full covariate adjustment. Significance was set to FDR&lt;0.05. Results: A total of 862 and 126 proteins were significantly associated with ANGPTL3/8 at baseline or post-training, respectively, with 80 proteins associated at both time points, including PCSK9 and PLTP ( Figure 1A ). Conversely, 46 proteins were only associated with ANGPTL3/8 at post-training, 23 of which whose levels significantly changed with training including NRP1, ghrelin, HHIP, and APOA1. A total of 433 and 71 proteins were significantly associated with ANGPTL4/8 at baseline or post-training, respectively, with 46 proteins associated with both time points ( Figure 1B ). A total of 25 proteins were only associated with ANGPTL4/8 at post-training, 12 of which whose levels significantly changed with training including ghrelin, COL6A2, and MMP16. Conclusions: We identified a subset of proteins uniquely associated with exercise-induced changes in ANGPTL3/8 and 4/8. Thus, the responsiveness of ANGPTL3/8 and 4/8 to regular exercise may be related to cholesterol esterification, lipoprotein remodeling, inflammatory response, and regulation of fibrinolysis and coagulation among other biological pathways.