Publications

This study describes the association between a BamHI polymorphism located in the subunit 5 of the NADH dehydrogenase gene of mtDNA, ˙VO2 max, and its response to a standardized 20-week endurance training program. Fiftyeight adult females and 55 males of Caucasian descent (52 ± 5 yrs, mean ± SD) of the HERITAGE Project (MSSE 27:721, 1995) took part in the study. mtDNA was extracted and amplified between bp13176 and 13729 by PCR and digested with the restriction endonuclease BamHI. ˙VO2max was measured during maximal stationary cycle ergometer tests. Initial˙VO2max values were 2.11 ± 0.61 L·min-1 or 26.2±5.8 ml/kg·min-1 while the increment with training reached 0.32 ± 0.21 L·min-1. Seventeen subjects (15%) carried a mutation at the restriction site (BamHI-morph 3). There was no gender difference in the frequency of the mutation. No associations were found between the BamHI polymorphism and ˙VO2max (L·min-1 and ml/kg·min-1) values before, after or in response to training. There was no difference between high (>90th%ile) and low(<10th%ile) responders in terms of mutation frequency for any of the phenotypes. These results do not replicate the findings of a previous study(MSSE 23:177, 1991) and suggest the need for further research on the significance of this particular mutation for aerobic performance, if any.

The beneficial effects of regular physical activity on insulin sensitivity (SI) and glucose tolerance are well documented, with considerable heterogeneity in responsiveness to exercise training (ET). To find novel candidate genes for ET-induced improvement in SI, we used microarray technology. Total RNA was isolated from vastus lateralis muscle before and after 20 wk of exercise from individuals participating in the HERITAGE Family Study. SI index was derived from a frequently sampled intravenous glucose tolerance test using MINMOD Millennium software. Sixteen subjects were selected: eight showing no changes in SI (low responders, LSIR) and eight displaying marked improvement in SI (high responders, HSIR) with ET. The SI increase was about four times greater in HSIR compared with LSIR (+3.6 +/- 0.5 vs. -1.2 +/- 0.5 microU.ml(-1).min(-1), mean +/- SE), whereas age, body mass index, percent body fat, and baseline SI were similar between the groups. Triplicate microarrays were performed, comparing pooled RNA with HSIR and LSIR individuals for differences in gene expression before and after ET using in situ-generated microarrays (18, 861 genes). Array data were validated by quantitative RT-PCR. Almost twice as many genes showed at least twofold differences between HSIR and LSIR after training compared with pretraining. We identified differentially expressed genes involved in energy metabolism and signaling, novel structural genes, and transcripts of unknown function. Genes of interest upregulated in HSIR include V-Ski oncogene, four-and-a-half LIM domain 1, and titin. Further study of these novel candidate genes should provide a better understanding of molecular mechanisms involved in the improvement in insulin sensitivity in response to regular exercise.

Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises important statistical issues. In the process of analyzing data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R, and K656N) of LEPR with body mass index (BMI; kilograms divided by the square of the height in meters) and waist circumference (WC), we encountered the following methodological challenges: data on relatives, missing data, multivariate analysis, multiallele analysis at multiple loci, heterogeneity, and epistasis. We propose herein statistical methods and procedures to deal with such issues. With a total of 3263 related and unrelated subjects from diverse ethnic backgrounds such as African-American, Caucasian, Danish, Finnish, French-Canadian, and Nigerian, we tested effects of individual alleles; joint effects of alleles at multiple loci; epistatic effects among alleles at different loci; effect modification by age, sex, diabetes, and ethnicity; and pleiotropic genotype effects on BMI and WC. The statistical methodologies were applied, before and after multiple imputation of missing observations, to pooled data as well as to individual data sets for estimates from each study, the latter leading to a metaanalysis. The results from the metaanalysis and the pooling analysis showed that none of the effects were significant at the 0.05 level of significance. Heterogeneity tests showed that the variations of the nonsignificant effects are within the range of sampling variation. Although certain genotypic effects could be population specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or waist circumference in the general population.

No abstract is provided for this article.

The aim of this study was to investigate whether there are familial influences on cortisol levels at baseline and in response to endurance exercise training and, if so, whether there is evidence for a major gene effect. There were 476 white individuals in 99 nuclear families and 247 black individuals in 105 families with valid cortisol data in the HERITAGE Family Study. Data adjustments were carried out separately in each of 8 sex by generation by race groups, using stepwise multiple regression procedures. The familial factors underling the variability in baseline cortisol (log-transformed and adjusted for age and baseline body mass index [BMI]) and its training response (post-training minus baseline, adjusted for age, baseline BMI, and the baseline cortisol value) were assessed by estimating familial correlations and carrying out segregation analysis. In the white sample, significant familial resemblance was detected for both baseline cortisol and the training response, with maximal heritabilities of 38% and 32%, respectively. However, significant familial correlations were not detected for either cortisol phenotype in the black sample, perhaps owing, in part, to the much smaller family sizes. Results of segregation analysis of the white sample provided evidence for Mendelian additive genes influencing baseline cortisol and its training response. The major genes accounted for 33% and 31% of the variance for baseline cortisol and the training response with 48% and 5% of the sample homozygous for the genotype leading to high values, respectively. In conclusion, we found significant familial effects influencing levels of baseline cortisol and its training response in the white sample. The putative major gene effects appear to explain most of the observed familial resemblance, this will motivate further linkage and association studies.

1900 Several lines of evidence suggest that the transforming growth factor beta-1 (TGFB1) gene may play an important role in the regulation of blood pressure (BP). The possible role of TGFB1 in the acute response to exercise remains unknown. This study examines the association between a DNA polymorphism in the TGFB1 gene and the acute systolic (S) and diastolic (D) BP response to submaximal and maximal cycle ergometer tests. The subjects were 190 sedentary unrelated Caucasians (females=93; males=97; mean age=53 yrs.) participating in the HERITAGE Family Study. The TGFB1 gene polymorphism in exon 1 (Leu10-Pro) was detected by PCR and digestion with the MspA1 I restriction enzyme. Allele and genotype frequencies were not significantly different between genders. Significant (P<0.04) differences in SBP values (at 60% and 80% of VO2max and at VO2max) adjusted for age, body mass index and gender were observed among the TGFB1 genotypes. Leu homozygotes demonstrated a significantly lower SBP (164, 183, and 198 mmHg) than heterozygotes (170, 189, and 206 mmHg) or Pro homozygotes (173, 195 and 211 mmHg). In conclusion, these results indicate a lower SBP response in carriers of the Leu allele (P<0.01) and suggest that the MspA1 I TGFB1 polymorphism is associated with the acute SBP response to submaximal and maximal exercise in the sedentary state.

Background: Mass spectrometry (MS) profiling has identified over 250 proteins associated with HDL that are thought to underlie the diverse atheroprotective properties of HDL particles and thus may be important biomarkers of cardiovascular disease (CVD) risk. Likewise, recent studies have identified circulating plasma proteins as biomarkers of CVD risk factors and health outcomes. However, few studies have compared the HDL proteome with the circulating plasma proteome. Purpose: The purpose of this analysis was to examine the relationship between the abundance of individual proteins measured in whole plasma and the HDL-sized plasma fraction. Methods: We examined the HDL-sized and circulating plasma proteomes in 156 Black (30%) and White men and women (61%) from the HERITAGE Family Study. HDL was isolated from plasma via gel filtration chromatography and untargeted MS analysis was performed via nano-HPLC-MS/MS. The whole plasma proteome was measured using a modified aptamer (SOMAscan) assay. The correlations between protein abundances in HDL and whole plasma were examined for 101 HDL-associated proteins present in at least 40% of the sample. Results: The abundance of 56 proteins in HDL-sized and whole plasma were significantly (5% FDR) correlated with the strongest correlation for Haptoglobin levels (r=0.83, p=1.1x10 -40 ) ( Table 1 ). The remaining significant correlations ranged from weak to moderate (r= 0.18-0.64) and were found among a mix of frequently and occasionally observed HDL proteins. Discussion: We found that protein abundance measured in HDL-sized and whole plasma were moderately to strongly correlated for several proteins, whereas 45% of protein levels showed no association between HDL-sized and whole plasma fractions. Given the inherit differences in measurement techniques and sources of proteins, it appears that the plasma HDL-sized proteome is mostly distinct from the circulating whole plasma proteome as measured by the SOMAscan assay.

Background Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. Objectives We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. Data sources Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. Study Eligibility Criteria Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. Methods We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. Results Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. Conclusions Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

This study examined the association between a DNA polymorphism in the muscle-specific creatine kinase (CKMM) gene and VO2max response(Δ) to a standardized 20-week endurance training program. The subjects were 160 unrelated Caucasians (females = 80; males = 80; age = 52±5 yrs, mean±SD) of the HERITAGE Family Study. The CKMM polymorphism was detected by PCR and digestion with the Ncol restriction enzyme. VO2max was measured during maximal stationary cycle tests. Initial VO2max was 2119±608 ml·min-1 or 26±6 ml·kg-1·min-1 while the Δ reached 323±204 ml·min-1, but with a gender difference(women=283±177 ml·min-1; men=363±223 ml·min-1; t=2.5, p=0.01). Allele and genotype frequencies were not significantly different between genders. Δ values adjusted for age, gender, initial VO2max and body mass were characterized by genotype differences (F=8.4, p=0.0004). Homozygotes for the rare 1170 bp allele demonstrated a significantly lower Δ (103±201 ml·min-1, n= 12) than heterozygotes (Δ=351±216 ml·min-1; n=70) or homozygotes (Δ =331±174 ml·min-1, n=78) for the common 985+ 185 bp allele. These results indicate an almost three-fold lower VO2max response to endurance training in homozygotes for the rare 1170 bp allele and suggest that the muscle-specific creatine kinase Ncol polymorphism is associated with the VO2max response to endurance training.

No abstract is provided for this article.

No abstract is provided for this article.

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.