Publications

Genotype imputations based on 1000 Genomes (1KG) Project data have the advantage of imputing many more SNPs than imputations based on HapMap data. It also provides an opportunity to discover associations with relatively rare variants. Recent investigations are increasingly using 1KG data for genotype imputations, but only limited evaluations of the performance of this approach are available. In this paper, we empirically evaluated imputation performance using 1KG data by comparing imputation results to those using the HapMap Phase II data that have been widely used. We used three reference panels: the CEU panel consisting of 120 haplotypes from HapMap II and 1KG data (June 2010 release) and the EUR panel consisting of 566 haplotypes also from 1KG data (August 2010 release). We used Illumina 324,607 autosomal SNPs genotyped in 501 individuals of European ancestry. Our most important finding was that both 1KG reference panels provided much higher imputation yield than the HapMap II panel. There were more than twice as many successfully imputed SNPs as there were using the HapMap II panel (6.7 million vs. 2.5 million). Our second most important finding was that accuracy using both 1KG panels was high and almost identical to accuracy using the HapMap II panel. Furthermore, after removing SNPs with MACH Rsq <0.3, accuracy for both rare and low frequency SNPs was very high and almost identical to accuracy for common SNPs. We found that imputation using the 1KG-EUR panel had advantages in successfully imputing rare, low frequency and common variants. Our findings suggest that 1KG-based imputation can increase the opportunity to discover significant associations for SNPs across the allele frequency spectrum. Because the 1KG Project is still underway, we expect that later versions will provide even better imputation performance.

The associations of the C34T polymorphism of the adenosine monophosphate deaminase 1 ( AMPD1) gene with cardiorespiratory phenotypes were tested during cycling exercise at absolute and relative power outputs progressing to exhaustion before and after endurance training for 20 wk in the HERITAGE Family Study cohort ( n = 779). Since no blacks were mutant homozygotes (TT), only whites were considered for analysis (400 normal homozygotes, CC; 97 heterozygotes, CT; and 6 TT). For sedentary state, cycling at the absolute power output of 50 W resulted in a higher rating of perceived exertion in TT ( P < 0.0001). At the relative intensity of 60% of V̇o 2 max , stroke volume was lower in TT ( P < 0.05). Maximal values for power output, systolic blood pressure, heart rate, V̇co 2 , and respiratory exchange ratio were lower in TT ( P < 0.05). The cardiorespiratory training response at 50 W and at 60% of V̇o 2 max was similar across C34T-AMPD1 genotypes. However, the maximal values for ventilation, V̇o 2 , and V̇co 2 during exercise increased less in TT ( P < 0.01). The results indicate that subjects with the TT genotype at the C34T AMPD1 gene have diminished exercise capacity and cardiorespiratory responses to exercise in the sedentary state. Furthermore, the training response of ventilatory phenotypes during maximal exercise is more limited in TT.

Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP).In 392 women with wide age (18-69 years) and body size (BMI: 17 to 90 kg/m(2) ) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features. Gene expression of C3 (ASP precursor) and related receptors C5L2, C3aR and C5aR in subcutaneous and omental adipose tissues was measured in a subset.Acylation stimulating protein correlated negatively with concentrations of estradiol (P < 0·0001), adiponectin (P < 0·001) and apolipoprotein A1 (P < 0·001) and positively with apolipoprotein B levels (P < 0·001), systolic blood pressure (P < 0·001), waist circumference (P < 0·001), and triglyceride concentrations (P < 0·01). In age-matched groups of lean, overweight, metabolically healthy obese (MHO) and obese with metabolic syndrome (MSO), there was a stepwise increase in ASP levels (P < 0·001) while concentrations of adiponectin (P < 0·0001) and estradiol (P < 0·001) but not those of progesterone decreased. Progesterone but not estradiol levels correlated positively with C3 gene expression in omental adipose tissue (P < 0·05) and negatively with C5L2 expression in both omental (P < 0·01) and subcutaneous (P < 0·05) adipose tissues.Our results are consistent with the concept that sex hormones differentially influence circulating ASP and adipose tissue gene expression of its related proteins in a depot-specific manner. ASP may play a role in the regulation of regional fat metabolism through interactions with sex hormones in women.

Unknown

Abdominal visceral fat (AVF) is an obesity-related phenotype thought to be associated with insulin resistance, diabetes mellitus, and atherosclerosis. Significant genetic influences on both AVF and insulin levels have been reported. However, information is lacking as to whether common genetic influences on AVF and insulin levels exist. AVF was assessed by computed tomography scan, and fasting insulin was measured by RIA in 512 members of 98 sedentary Caucasian families participating in the HERITAGE Family Study. Baseline data, collected before exercise training, were used in the present investigation. A bivariate familial correlation model was applied to evaluate whether there are familial influences that are common to insulin and AVF before and after adjustment for total fat mass (FM), and to assess the overall heritability of insulin and AVF. The maximal heritability for AVF, before and after adjustment for total FM, was 42% and 50%, respectively; and for insulin, it was 21%. Interestingly, 29% of the familial influences on insulin were also common to AVF, whereas 14% of the familial influences on AVF were shared by insulin. Furthermore, after AVF was adjusted for total FM, these common familial influences were increased to 48% and 20%. Genes and/or familial nongenetic factors with pleiotropic effects seem to influence both AVF and plasma insulin levels to a certain degree. Genes involved in the regulation of lipid storage and mobilization in the abdominal fat depot are potential candidates for these genetic pleiotropic effects.

RANKINEN, T., L. PÉRUSSE, R. RAURAMAA, M. A. RIVERA, B. WOLFARTH, and C. BOUCHARD. The human gene map for performance and health-related fitness phenotypes: the 2001 update. Med. Sci. Sports Exerc., Vol. 34, No. 8, pp. 1219–1233, 2002. This review presents the 2001 update of the human gene map for physical performance and health-related phenotypes. It is based on scientific papers published by the end of 2001. Association studies with candidate genes, genome-wide scans with polymorphic markers, and single gene defects causing exercise intolerance to variable degrees are included. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed, but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, there were 29 loci depicted on the map. The 2001 map includes 71 loci on the autosomes and two on the X chromosome. Among these genes or markers, 24 are from prior publications on exercise intolerance and four relate to other pathologies. Finally, 13 sequence variants in mitochondrial DNA have been shown to influence relevant fitness and performance phenotypes.

No abstract is provided for this article.

No abstract is provided for this article.

Potential correlates of plasma very-low-density lipoprotein (VLDL) concentration and composition were studied in a sample of 75 premenopausal women. Fasting plasma free fatty acid (FFA) levels, as well as plasma glucose and insulin levels in the fasting state and during an oral glucose tolerance test, displayed significant positive correlations with plasma triglyceride (TG) and VLDL-TG levels (P < .005). Plasma post-heparin lipoprotein lipase (LPL) activity, measured in a subsample of 31 women from the original sample, was negatively correlated with plasma TG, VLDL-cholesterol (CHOL), VLDL-TG, and VLDL-apolipoprotein (apo) B concentrations (.005 > P < .05). Multivariate analyses showed that, after LPL was considered, the insulin area was the only other metabolic variable studied that was significantly correlated with VLDL-apo B concentration, whereas fasting FFA levels were significantly correlated with plasma TG and VLDL-TG levels. ANOVA revealed that plasma VLDL-CHOL, VLDL-TG, and VLDL-apo B levels were not associated with the glucose area, but were significantly associated with the insulin area (P < .005). When the effect of insulin area was controlled for, the plasma FFA levels did not contribute significantly to the variance in VLDL-CHOL and VLDL-apo B, but showed an independent effect on VLDL-TG levels (P < .05). Finally, stepwise multiple regression analyses indicated that once the variance explained by plasma LPL activity and by the insulin area was considered, no other metabolic variable could account for the variation in VLDL-CHOL and VLDL-apo B levels, whereas fasting FFA levels explained a further 5% of the VLDL-TG variance and one third of the variance observed in the VLDL-TG/apo B ratio. These results suggest that high plasma insulin levels and a low post-heparin plasma LPL activity are conditions associated with an increased concentration of VLDL, whereas high FFA levels are rather associated with an enrichment of VLDL with triglycerides.

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

This review of the exercise genomics literature emphasizes the highest quality articles published in 2011. Given this emphasis on the best publications, only a small number of published articles are reviewed. One study found that physical activity levels were significantly lower in patients with mitochondrial DNA mutations compared with controls. A two-stage fine-mapping follow-up of a previous linkage peak found strong associations between sequence variation in the activin A receptor, type-1B (ACVRIB) gene and knee extensor strength, with rs2854464 emerging as the most promising candidate polymorphism. The association of higher muscular strength with the rs2854464 A allele was confirmed in two separate cohorts. A study using a combination of transcriptomic and genomic data identified a comprehensive map of the transcriptomic features important for aerobic exercise training-induced improvements in maximal oxygen consumption, but no genetic variants derived from candidate transcripts were associated with trainability. A large-scale de novo meta-analysis confirmed that the effect of sequence variation in the fat mass and obesity-associated (FTO) gene on the risk of obesity differs between sedentary and physically active adults. Evidence for gene-physical activity interactions on type 2 diabetes risk was found in two separate studies. A large study of women found that physical activity modified the effect of polymorphisms in the lipoprotein lipase (LPL), hepatic lipase (LIPC), and cholesteryl ester transfer protein (CETP) genes, identified in previous genome-wide association study reports, on HDL cholesterol. We conclude that a strong exercise genomics corpus of evidence would not only translate into powerful genomic predictors but also have a major effect on exercise biology and exercise behavior research.