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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. [ABSTRACT FROM AUTHOR]

The article presents a review of literature on exercise genomics. It discusses 2010 articles focusing on physical activity, endurance performance, muscular strength and power, diposity, hemodynamic traits, and glucose and insulin metabolism. It cites that J. R. Ruiz and colleagues' study of the potential for naming a "power-oriented polygenic" enables the use of a "total genotype score" (TGS) approach. N. T. Jenkins and colleagues investigated the link of common sequence variants in the perilipin (PLIN) gene with aerobic fitness, body fatness, and related risk factors of cardiovascular disease. It mentions that a major strength of J. J. Mann and colleagues' study of hemodynamic traits is the sample size of men. It concludes that there is an urgent need for studies with large sample sizes.

Perilipins are lipid droplet-coating proteins that regulate intracellular lipolysis in adipocytes. A haplotype of two perilipin gene (PUN) single nucleotide polymorphisms, 13041A>G and 14995A>T, has been previously associated with obesity risk. Furthermore, the available data indicate that this association may be modified by sex. We hypothesized that this haplotype would associate with body fatness, aerobic fitness, and a number of cardiovascular (CV) risk factor phenotypes before and after a 6-mo endurance exercise training program in sedentary older Caucasians. The major haplotype group (13041A114995A; n = 57) had significantly lower body mass index (BMI) and body fatness compared with noncarriers of the AA haplotype (n = 44) before the training intervention. Training improved body composition in both groups, but fatness remained higher in noncarriers than AA carriers after training. This fat retention in noncarriers blunted their maximal oxygen uptake (VO2max) adaptation to training. Female noncarriers had substantially higher concentrations of several conventionally and NMR-measured HDL-C subfractions than male noncarriers before and after training, but only minimal differences were found between the sexes in the AA haplotype group. Haplotype group differences in baseline and after-training responses to an oral glucose tolerance test (OGTT) also differed by sex, as noncarrier men had the highest baseline area under the insulin curve (insulin AUC), but were the only group to significantly improve insulin AUC with training. The insulin sensitivity index and plasma glucose responses to the OGTT were more favorable in AA carriers than noncarriers before and after training. Overall, our findings suggest that PUN variation explains some of the interindividual differences in the response of obesity and CV phenotypes to exercise training. Furthermore, these data contribute to the growing under- standing of PUN as a candidate gene for human obesity and the cardiometabolic consequences of excess adiposity. [ABSTRACT FROM AUTHOR]

Abstract: The objective of the study was to determine whether ethnicity interacts with the APOE genotype to influence conventionally measured high-density lipoprotein cholesterol (HDL-C) subfraction levels and nuclear magnetic resonance–measured (HDLNMR-C) particle size at baseline and after training, and the changes with training. After a 6-week dietary stabilization period, men and postmenopausal women 50 to 75 years old underwent baseline testing (NMR lipid, maximum oxygen consumption, body composition, and genotyping assessments). Tests were repeated after completing 24 weeks of endurance exercise training. At baseline, APOE2/3 blacks had significantly larger particle size (P < .001) and higher total HDLNMR-C particle concentration (P = .006) than whites. After 6 months of endurance exercise training, APOE2/3 blacks maintained a significantly larger HDLNMR-C particle size (P < .001) and particle concentration of the large HDLNMR-C than APOE2/3 whites (P < .001). In multivariate analyses of variance adjusted for demographic and environmental confounding factors and for training-induced changes in lean body mass and intraabdominal fat, the model explained approximately 33% of the observed variability in training-induced improvements in HDLNMR-C particle size (P = .002), with APOE2/3 blacks having a greater increase in training-induced changes in HDLNMR-C particle size. In a separate but similarly adjusted model for conventionally measured HDL2-C, the model explained approximately 49% of the observed variability in training-induced changes in HDL2-C. Ethnicity interacted with the E2/3 genotype at the APOE gene locus to influence higher baseline and after-training levels, and greater exercise training–induced improvements in the advantageous HDL-C subfractions in blacks than in whites. APOE2/3 blacks may benefit more from aerobic fitness to reduce cardiovascular risk. [Copyright &y& Elsevier]

The lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized low-density lipoprotein. LOX-1 can be cleaved from the cell surface and released as soluble LOX-1 (sLOX-1), and elevated sLOX-1 levels may be indicative of atherosclerotic plaque instability. We examined associations between the LOX-1 gene 3′UTR-C/T and G501C polymorphisms and plasma sLOX-1 levels in 97 healthy older men and women. The frequencies for the 3′UTR-T and 501C alleles were 46 and 10%, respectively. Plasma sLOX-1 levels were significantly higher in the 3′UTR CC genotype group compared with both the CT ( P= 0.02) and TT genotype groups ( P= 0.002). Plasma sLOX-1 levels were also significantly higher in the 501GC genotype group compared with the GG genotype group ( P= 0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3′UTR-C/T and G501C polymorphisms. These associations remained significant after adjusting for age, sex, race and body mass index. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women. [ABSTRACT FROM AUTHOR]

To examine the influence of insulin-like growth factor (IGF) pathway gene polymorphisms on muscle mass and strength responses to strength training (ST), we studied 128 White and Black men and women before and after a 10-wk single-leg knee extension ST program. One-repetition maximum strength, muscle volume (MV) via computed tomography, and muscle quality (MQ) were assessed at baseline and after 10 wk of ST. There was a significant combined IGFI cytosine adenine (CA) repeat gene effect, which included both the IGFI CA repeat main effect and IGFI CA repeat X PPP3RI insertion-deletion (l/D) gene X gene interaction effect, on the changes in strength (P < 0.01) and MQ (P < 0.05) with ST. There was a trend for a significant gene X gene interaction between IGFI CA repeat and PPP3RI l/D for changes in strength (P = 0.07) and MQ (P = 0.06) with ST. The influence of the PPP3RI A-202C gene polymorphism on change in MV with ST approached significance (P = 0.06). The IGFI CA repeat polymorphism had a significant influence on the change in strength and MV combined with ST (P < 0.05), whereas the influence of the PPP3RJ l/D polymorphism approached significance (P = 0.08). There were no associations between the IGFBP3 A-202C gene polymorphism and the muscle phenotypic responses to ST. These data suggest that two of the three IGF pathway gene polymorphisms identified in this study influence muscle phenotypic responses to ST in both Black and White older men and women. [ABSTRACT FROM AUTHOR]

In endothelial cells, NF-κB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase (NOS3) gene expression. We investigated whether NF-κ light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (-94NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage 1 hypertensive individuals before and after a 6-too supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the -94NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity. [ABSTRACT FROM AUTHOR]

In its role as an endothelial cell proliferation and migration factor, vascular endothelial growth factor (VEGF) can affect peripheral circulation and therefore impact maximal oxygen consumption (V̇o2 max). Because of the role of VEGF, and because variation in the VEGF gene has the ability to alter VEGF gene expression and VEGF protein level, we hypothesized that VEGF gene polymorphisms are related to VEGF gene expression in human myoblasts and V̇o2 max before and after aerobic exercise training. We analyzed the effects of the VEGF -2578/ -1154/-634 promoter region haplotype on VEGF gene expression by using a luciferase reporter assay in cultured human myoblasts and found that the AAG and CGC haplotypes resulted in significantly higher hypoxia-stimulated VEGF gene expression than the AGG and CGG haplotypes. Consistent with these results, we found that individuals with at least one copy of the AAG or CGC haplotype had higher V̇o2 max before and after aerobic exercise training than did subjects with only the AGG and/or CGG haplotype. In conclusion, we found that VEGF-2578/-1154/-634 haplotype impacts VEGF gene expression in human myoblasts and is associated with V̇o2 max. These results have potential implications for aerobic exercise training and may prove relevant in the study of pathological conditions that can be affected by angiogenesis, such as coronary artery disease and peripheral artery disease. [ABSTRACT FROM AUTHOR]

Systemic oxidative stress plays a role in many degenerative diseases. Although regular physical activity has been known as the most effective nonpharmacological intervention to alleviate the oxidative stress, the beneficial effect varies between individuals. We investigated whether NADPH oxidase p22phox gene C242T and A640G polymorphisms are associated with systemic oxidative stress level response to exercise training (ExTr). Fifty-nine sedentary middle-aged to older Caucasians with relatively high cardiovascular disease risk factors underwent a 6-mo standardized ExTr program. Body mass index, plasma lipoprotein-lipid profiles, cardiovascular fitness, and plasma thiobarbituric acid reactive substances (TBARS) were measured before and after ExTr. Demographic and initial levels of cardiovascular disease risk factors were similar among genotype groups for both polymorphisms. Overall, TBARS was decreased by 16% with ExTr in the entire group (P < 0.001). There was no significant difference in TBARS changes with ExTr among the C242T genotype groups. However, A allele carriers showed greater reduction in TBARS than noncarriers at the A640G locus (P = 0.05). There was a significant interaction (P = 0.05) between ExTr and A640G polymorphism in TBARS changes with ExTr. This interaction remained after accounting for age and baseline TBARS level. Furthermore, diplotype analysis showed that TBARS was decreased to a greater extent in the C242/A640 haplotype carriers compared with the noncarriers (P < 0.05). We found that p22phox polymorphisms, especially A640G, were associated with differential changes in systemic oxidative stress with aerobic exercise training. [ABSTRACT FROM AUTHOR]

A polymorphism in the IL-6 gene, a G-to-C substitution 176 bp upstream of the ATG translation initiation site, has been associated with diabetes prevalence and insulin resistance. Interventions including exercise training are frequently used to modify cardiovascular disease risk factors. Consequently, this project examined associations between the IL-6 -174 genotype and oral glucose tolerance test outcomes in 50- to 75-yr-old sedentary men and postmenopansal women before and after aerobic exercise training. Among the 87 individuals who started the study, 56 were retested after 6 mo of aerobic exercise training. Subject characteristics at baseline did not differ between the IL-6 genotype groups with the exception of fasting glucose, which was higher (P = 0.02, covariates age, gender, and ethnicity) in the CC genotype group. The training-induced change in glucose area under the curve during the oral glucose tolerance test varied between the IL-6 -174 genotype groups (P = 0.05, covariates age, gender, ethnicity, baseline glucose area under the curve, and percent body fat change) with a significant decrease occurring only in the GG genotype group. Insulin outcomes did not differ among the groups at baseline or after training. Training-induced changes in weight, percent body fat, maximal oxygen consumption, fasting glucose, and an insulin sensitivity index also changed similarly among the genotype groups. In conclusion, fasting glucose and the extent to which glucose tolerance changes with exercise training may be influenced by the IL-6 -174 gene polymorphism. [ABSTRACT FROM AUTHOR]

Assesses the effects of coagulation factor VII (FVII) gene polymorphisms, lipid-related polymorphisms and exercise-training induced plasma lipoprotein lipid changes on FVII level changes with exercise training in middle- to older-aged men and women. Stabilization of sedentary men and women on a low-fat diet with baseline testing; Decrease in plasma FVII-Ag changes with exercise training.

The article presents a study that investigates the influence of C242T and A640G polymorphisms as well as of six months aerobic exercise training in Pre and Stage 1 hypertensive adults. It notes that 94 sedentary men and women participated in the study and asserts that they follow the low-nitrate diet recommended by American Heart Association. It reveals that there is no significant difference in the characteristics of the subject; however, a significant difference in urinary 8-iso-prostaglandin F (PGF) 2 Α among the genotype groups is observed. It asserts that aerobic exercise training decreases enzyme activity, improves endothelial function, and greatly affects the oxidative stress responses of the subject.

Abstract: Background: High-density lipoprotein cholesterol (HDL-C) and its subfractions are modifiable with exercise training and these responses are heritable. The interleukin-6 (IL6)-174G/C polymorphism may be associated with HDL-C levels. We hypothesized that the IL6-174G/C polymorphism would be associated with plasma HDL-C response to exercise training. Methods and results: Sixty-five 50- to 75-year-olds on a standardized diet were studied before and after 24 weeks of aerobic exercise training. Significant differences existed among genotype groups for change with exercise training in HDL-C, HDL3-C, integrated HDL4,5NMR-C, and HDLsize. The CC genotype group increased HDL-C more than the GG (7.0 ± 1.3 v. 1.0 ± 1.1 mg/dL, p = 0.001) and GC groups (3.3 ± 0.9 mg/dL, p = 0.02); for HDL3-C, the CC group increased more than the GG (6.1 ± 1.0 v. 0.9 ± 0.9, mg/dL p &#60; 0.001) and GC groups (2.5 ± 0.7 mg/dL, p = 0.006). Integrated HDL4,5NMR-C increased more in the CC than GG group (6.5 ± 1.6 mg/dL v. 1.0 ± 1.3 mg/dL, p = 0.01), as did HDLsize compared to the GG (CC: 0.3 ± 0.1 v. GG: 0.1 ± 0.1 nm, p = 0.02) and GC (0.0 ± 0.0 nm, p = 0.007) groups. Conclusions: IL6 genotype is associated with HDL-C response to exercise training. [Copyright &y& Elsevier]