Publications

KCNJ11 GENE POLYMORPHISM AND ELITE ENDURANCE ATHLETE STATUS

The K+ inwardly rectifying channel of the subfamily J member 11 (KCNJ11) gene is widely expressed in cardiac, vascular-smooth and skeletal muscles. These tissues are highly relevant in cardiorespiratory endurance. PURPOSE to examine the possible association between a KCNJ11 gene polymorphism and elite endurance athlete (EEA) status. METHODS We examined the DNA of 184 male EEA (VO2max ≥ 75 ml/kg/min) and 113 male controls (CON; VO2max ≤ 49 ml/kg/min). Subject in both groups were matched by country of origin. Polymerase chain reaction amplification targeted a region of 267 base pairs, in codon 23, which included the polymorphic site (C→T transition; glutamate→lysine). RESULTS The three expected KCNJ11-BanII genotypes were observed in the EEA and CON. Allelic frequencies (EEA; C = 61%, T = 39% and CON; C = 50%, T = 50%) were significantly different between groups (χ2 = 6.2, df = 1, P = 0.01). Genotypic frequencies (EEA; CC = 37%, CT = 48%, TT = 15% and CON; CC = 29%, CT = 43%, TT = 28%) were also significantly different between EEA and CON (χ2 = 7.6, df = 2, P = 0.02). CONCLUSION Thse findings suggest that DNA sequence variation in the KCNJ11 gene is part of the complex genotype associated with the elite endurance athlete status. Supported by CRC-RCMI UPR-MSC Grant #1P20RR11126, RCMI Basic Sciences #G12RR03051 and MBRS-RISE R25GM61838.

Heart Rate Recovery after Maximal Exercise Is Associated with Acetylcholine Receptor M2 (CHRM2) Gene Polymorphism

Determinants of heart rate (HR) recovery after exercise are not well known, although attenuated HR recovery is associated with an increased risk of cardiovascular mortality. PURPOSe: Since acetylcholine receptor subtype M2 (CHRM2) plays a key role in cardiac chronotropic response, we tested the hypothesis that in healthy individuals the CHRM2 gene polymorphisms are associated with HR recovery one minute after the termination of maximal exercise test, both before and after endurance training. METHODS: The study population consisted of sedentary males and females (n=95, 42±5 yr) assigned either to a training (n=80) or a control group (n=15). A 2-week laboratory-controlled endurance training program included five 40-min sessions a week at 70–80% of the maximum HR. RESULTS: The HR recovery differed between the Intron 5 rs324640 genotypes at baseline (C/C −33±10, C/T −33±7 and T/T −40±1 1 beats per minute (bpm), P=0.008). Endurance training further strengthened the association: the less common C/C homozygotes showed 6 and 12 bpm lower HR recovery than the C/T heterozygotes, and the T/T homozygotes (P=0.001), respectively. A similar association was found between an A/T transversion at the 3' UTR of the CHRM2 gene and HR recovery at baseline (P=0.025) and after endurance training (P=0.005). CONCLUSIONS: These data suggest that DNA sequence variation in the CHRM2 locus is a potential modifier of HR recovery in the sedentary state, and after short-term endurance training program in healthy individuals. Supported by the Medical Council of the Finnish Academy of Science, Helsinki, Finland and the Ministry of Education, Helsinki, Finland.

Genetics of Obesity: Etiologic Heterogeneity and Temporal Trends

Phenotypes devised to quantitate the degree of obesity have been the subject of many recent investigations, motivated by the increased risk of cardiovascular morbidity and mortality, largely through increased risk of diabetes, hypertriglyceridemia, changes in plasma lipoprotein profile and composition, and hypertension. The observation that the prevalence of obesity has been increasing in developed countries over the last half century is consistent with studies suggesting the importance of non-shared environmental influences. A model to assess temporal trends in familial correlations under multifactorial inheritance has been developed in the context of path analysis, using a simple tau model. Identification of the determinants of human obesity is a complex problem and poses numerous research challenges. It is clear that each of polygenic, shared environmental, unique environmental, and major gene factors all have been implicated in various studies, and the evidence for the presence and magnitude of each is not entirely consistent across all studies.

[Intracranial hypertension and cerebral hypoperfusion, frequent complications in severe burns].

No abstract is provided for this article.

Consistency of fat mass–fat-free mass relationship across ethnicity and sex groups

The model developed by Forbes (1987) of how body fat mass (FM) and fat-free mass (FFM) change during periods of weight loss or gain (Δ body weight (BW)) assumed that they change in relationship to a constant C = 10·4, where ΔFFM/ΔBW = 10·4/(10·4+FM). Forbes derived C based on aggregated, cross-sectional data from a small sample of women. The objective of the present study was to reanalyse the relationship described by Forbes and to explore whether this relationship is consistent across ethnicity and sex groups using cross-sectional data from a large sample of white and African-American men and women. Baseline data from white and African-American men and women aged 18–60 years, who participated in a clinical study at the Pennington Biomedical Research Center since 2001 and who underwent dual-energy X-ray absorptiometry scans, were available for analysis. To overcome differences in BMI distributions among the ethnicity-by-sex groups, a stratified random sample of participants was selected within each group such that numbers in each BMI category ( < 25, 25–29·9, 30–34·9, 35–39·9, 40+ kg/m 2 ) were proportional to those within the group with the smallest sample size, yielding a sample of 1953 individuals. Linear regression models assessed the FM–FFM relationship across the four ethnicity-by-sex groups. The FM–FFM relationship varied little by ethnicity ( P = 0·57) or by sex ( P = 0·26). The constant describing the FM–FFM relationship was estimated to be 9·7 (95 % CI 9·0, 10·3). In conclusion, results from our large, biethnic sample of men and women found a FM–FFM relationship very close to that originally described by Forbes, absent of significant variability by ethnicity or sex.

GENOMIC SCAN FOR EXERCISE STROKE VOLUME AND CARDIAC OUTPUT IN THE HERITAGE FAMILY STUDY

A genome-wide linkage scan was performed to identify genomic regions influencing submaximal exercise cardiac output (Q) and stroke volume (SV) in the sedentary state and their responses to a standardized 20-week endurance training program. A total of 344 polymorphic markers were used and 292 pairs of siblings from 99 White nuclear families and 90 sibling pairs from 105 Black family units were available for the study. All subjects were healthy but sedentary at baseline. Two exercise tests at 50W were done before and after the training program, and Q and SV (Q50 and SV50, resp.) were measured twice during each test. Baseline phenotypes were adjusted for age, sex and body surface area (BSA). Training responses (post-training û baseline, Δ) were adjusted for age, sex, baseline BSA and baseline value of the phenotype. Linkage analysis was performed using a multipoint variance components model, as implemented in SEGPATH. In Whites, two chromosomal regions showed suggestive linkages with baseline SV50 (7q35-q36, 14q24.3-q31) and two QTLs were detected for baseline Q50 (14q21-q23, 17p13-p12). Both ΔSV50 and ΔQ50 showed suggestive linkage with markers at 2q31 (LODs 1.40 and 1.56, p-values 0.0056 and 0.0037, respectively). An additional QTL for ΔQ50 was detected at chromosome 20q13.2-q13.3 (LOD = 1.50, p = 0.0042). In Blacks, QTLs at 1p22-p13, 3q13, 10p15-p13 and 16q12-q21 were detected for baseline SV50 (LODs from 1.27 to 1.65, p-values from 0.0078 to 0.0029). Baseline Q50 showed linkages with markers at 10p15-p13 (LOD = 1.18, p = 0.010) and 13q11-q12.1 (LOD = 1.20, p = 0.0094). All QTLs include several potential candidate genes and therefore warrant further studies in the HERITAGE cohort and other studies. Supported by multiple grants from NIH-NHLBI

Androstane-3α,17β-Diol Glucuronide as a Steroid Correlate of Visceral Obesity in Men*

Plasma levels of androstane-3α,17β-diol glucuronide (3α-DIOL-G) and androsterone glucuronide (ADT-G) as well as testosterone and adrenal C19 steroid concentrations were measured in a sample of 80 men in whom visceral adipose tissue (AT) accumulation was also determined by computed tomography. Plasma 3α-DIOL-G concentrations showed significant positive correlations with total body fat mass (r = 0.31; P < 0.05) and percent body fat (r = 0.28; P < 0.05). Furthermore, plasma 3α-DIOL-G levels were significantly associated with visceral adipose tissue accumulation (r = 0.41; P < 0.0005) as well as fasting plasma insulin (r = 0.35; P < 0.005) and glycemic and insulinemic responses to an oral glucose load (r = 0.39; P < 0.0005 and r = 0.32; P < 0.005, respectively). However, associations between 3α-DIOL-G and plasma glucose-insulin homeostasis indexes were no longer significant after adjustment for visceral AT area. ADT-G levels were not significantly associated with any of the adiposity variables. Subjects matched for abdominal sc AT area but with either low or high levels of visceral AT area showed significant differences in 3α-DIOL-G concentrations (P < 0.05), whereas subjects with low or high levels of abdominal sc AT but similar levels of visceral AT had similar 3α-DIOL-G concentrations. Among men with high testosterone levels, subjects with reduced 3α-DIOL-G concentrations had lower visceral adipose tissue accumulation than subjects with increased 3α-DIOL-G levels. The present results indicate that plasma 3α-DIOL-G, but not ADT-G, is a steroid correlate of visceral obesity. Excess visceral adipose tissue and/or concomitant alterations in insulin levels or in vivo insulin action could be responsible for the increased 3α-DIOL-G formation observed in this condition.

Kcnj11 Gene Polymorphism And Endurance Performance Status In Hispanics

An association between a DNA sequence variant in the K+ inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene and elite endurance athlete status was recently reported (MSSE 35(5):S379, 2003). PURPOSE To examine the hypothesis of an association between the same KCNJ11 gene polymorphism and endurance performance status in Hispanics. METHODS DNA samples were successfully genotyped from 171 Hispanics subjects. Cases (n = 98) were long distance runners finishers in the highest 3 percentile, by age and gender, during their participation in an international marathon (42 km) race, while controls (n = 73) were subjects with severely compromised cardiorespiratory functions. The polymorphism was detected by PCR and digestion with Ban II endonuclease. RESULTS The three expected KCNJ11-BanII genotypes were observed in both genders and groups. These genotype frequencies, within each gender, were in Hardy-Weinberg equilibrium (X2, P>0.05) and not different (X2, P>0.05) different between genders. There was no gender difference (X2, P>0.05) in allelic frequencies. Chi-square analysis for the pooled data for both genders revealed significant differences in genotype (cases; TT = 8%, TC = 47%, CC = 45% and controls; TT = 28%, TC = 38%, CC = 34%; Chi-square = 7.7, df = 2, P = 0.02) and allele (Cases; T = 32%, C = 68% and Controls; T = 47%, C = 53%; Chi-square = 4.0, df = 1, P = 0.04) frequencies between the cases and controls. CONCLUSION As in previously shown (MSSE 35(5):S379, 2003) in Caucasians, an excess of the KCNJ11-BanII T allele is negatively associated with the complex phenotype of endurance performance status in Hispanics. Supported by CRC-RCMI 1P20RR11126, RCMI #G12RR03051, Comite de Fondismo: FPRA, Maraton Pacifico de Guardajara, and Maraton Popular de Madrid.

Effect of individual characteristics and aerobic training on the %HRR‐%<i>V̇</i>O₂R relationship

This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (V̇O2R) reserve either 1:1 or more accurate. Cycle ergometer data of the maximal incremental exercise tests performed by 450 healthy and sedentary participants (17-66 years) of the HERITAGE Family Study, grouped for sex, ethnicity, age, body fat, resting HR, and V̇O2max, were used to calculate the individual linear regressions between %HRR and %V̇O2R. The mean slope and intercept of the individual linear regressions of each subgroup were compared with 1 and 0 (identity line), respectively, using Hotelling tests followed by post-hoc one-sample t-tests. Two multiple linear regressions were also performed, using either the slopes or intercepts of the individual linear regressions as dependent variables and sex, age, resting HR, and V̇O2max as independent variables. The mean %HRR-%V̇O2R relationships of all subgroups differed from the identity line. Moreover, individual linear regression intercepts (8.9 ± 16.0) and slopes (0.971 ± 0.190) changed (p < 0.001) after 20 weeks of aerobic training (13.1 ± 11.1 and 0.891 ± 0.122). The multiple linear regressions could explain only 3.8% and 1.3% of the variance in the intercepts and slopes, whose variability remained high (standard error of estimate of 15.8 and 0.189). In conclusion, the %HRR-%V̇O2R relationship differs from the identity line regardless of individual characteristics and their difference increased after aerobic training. Moreover, due to the high interindividual variability, using a single equation for the whole population seems not suitable for representing the %HRR-%V̇O2R relationship of a given subject, even when several individual characteristics are considered.HighlightsThe association between %HRR and %V̇O2R is not 1:1 even when individuals are grouped by age, sex, ethnicity, body composition, HRrest, and V̇O2max.Using several subject characteristics to identify the individual's %HRR-%V̇O2R relationship does not meaningfully increase its prediction accuracy or reduce the interindividual variability of %HRR-%V̇O2R relationshipsUsing a single equation for the whole population is not suitable for representing the relationship of a given subject; hence, individual relationships should be preferred when prescribing the intensity of aerobic exercise.The individual %HRR-%V̇O2R relationship should be periodically assessed due to the potential training induced changes in the relationship.

Genetic basis of racial differences.

The purpose of this paper is (a) to present brief historical notes on the concept of race, (b) to define race in the context of evolutionary biology, (c) to quantify the extent of human genetic variation, (d) to estimate genetic differences within and between races, and (e) to comment on the implications of these concepts for racial differences in sport performance. Research shows that genetic variation in gene products and in the non-coding sequence of DNA is quite extensive in humans. Variation is found more frequently in non-coding DNA sequences than in coding exons, and while this variation does not influence the primary structure of the proteins, it may have considerable impact on gene expression. However, much of that genetic variation is shared by all human beings, and only about 10% is specific to races or populations within races. At this time, it is not possible to conclude satisfactorily the significance of these modest racial differences in genetic variation for racial differences in performance. It may turn out that this low level of genetic heterogeneity may have considerable implication for performance.

Exploring the underlying biology of intrinsic cardiorespiratory fitness through integrative analysis of genomic variants and muscle gene expression profiling

Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic V̇o

training in humans exercise maximal aerobic capacity following endurance Using molecular classification to predict gains in

3. Genetics and Olympic Athletes: A Discussion of Methods and Issues

No abstract is provided for this article.

Endurance Exercise TVaining Reduces Lp-PLA2 in Young White Adults

INTRODUCTION: High levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) have been identified as a risk factor for CHD. Endurance exercise training (EET) generally has positive effects on plasma lipids and biomarkers of inflammation. PURPOSE: To study its effect on Lp-PLA2. METHODS: Subjects were 706 participants in the biracial and two generational HERITAGE Family Study. Fasting plasma samples were drawn in the morning before and following 20 weeks of EET and analyzed for Lp-PLA2. EET was conducted 3 days/week and started at 55% of maximal oxygen uptake (VO2max) for 30 min/day. Intensity and duration were increased every 2 weeks up to 75% of VO2max and 50 min per session for the last 6 weeks. Duplicate measures of VO2max were obtained both pre- and post-training. Summary of RESULTS: VO2max increased by 17.6 ± 9.5% (mean ± SD) for the total sample demonstrating a substantial training response. Women had a greater percentage increase than men, but the increase for the total sample was independent of race and age. Lp-PLA2 decreased 4.0% (p<0.0001) from 275.7 ± 88.8 to 264.8 ± 85.9 ug/L in the total sample, and was unrelated to the change in total mass and fat mass. The decrease was substantially greater in whites (4.6%, p<0.0001) than in blacks (2.1%, p=0.16); in sons (4.1%, p=0.003) than in fathers (1.8%, p=0.38); and in daughters (5.6%, p<0.0001) than in mothers (3.0%, p=0.13). CONCLUSIONS: EET decreased Lp-PLA2 by 4.0% in the total sample. The decrease in Lp-PLA2 was demonstrated in whites, predominantly in the younger generation, but not in blacks. There were no differences in Lp-PLA2 changes by sex.

Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

Physical activity, fitness, and non-insulin-dependent (type II) diabetes mellitus.

No abstract is provided for this article.

Replication of 6 Obesity Genes in a Meta-Analysis of Genome-Wide Association Studies from Diverse Ancestries

Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10−7 for BMI, 1.80×10−6 for FM, and 5.29×10−4 for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10−3 to 4.94×10−2). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.

Human energy and nutrient balance.