Publications

A low maximal oxygen consumption (VO2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases VO2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts VO2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous VO2max response. Two independent preintervention RNA expression data sets were generated (n=41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in VO2max ("predictor" genes). The HERITAGE Family Study (n=473) was used for genotyping. We discovered a 29-RNA signature that predicted VO2max training response on a continuous scale; these genes contained approximately 6 new single-nucleotide polymorphisms associated with gains in VO2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., "reciprocal" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in VO2max, corresponding to approximately 50% of the estimated genetic variance for VO2max. In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. VO2max responses to endurance training can be predicted by measuring a approximately 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.

1907 It has been suggested that genetic variation at the ACE locus is associated with the performance phenotypes. However, problems with sample size, study designs and performance phenotypes cast doubt on these findings. We studied the association between the ACE insertion/deletion (I/D) polymorphism and several cardiorespiratory phenotypes measured before and after 20 weeks of endurance training in 474 sedentary Caucasians and 248 Blacks. Phenotypes measured were oxygen uptake and heart rate (HR) during maximal and submaximal (50 W, 60 % and 80 % of VO2max) exercise, maximal work rate (Wmax), systolic and diastolic blood pressure, rate pressure product (RPP), stroke volume and cardiac output during submaximal exercise (50 W and 60 %). The ACE I/D polymorphism was typed with the three-primer PCR method. Out of 184 tests performed on 46 phenotypes in 4 groups of participants, only five showed significant (p-values from 0.042 to 0.0008) associations with the ACE I/D polymorphism. In contrast to previous claims, in Caucasian offspring, the D/D homozygotes showed a 14 to 32 % greater increase in VO2max, VO2 at 80% and Wmax, and a 23 to 35% greater decrease in HR and RPP at 50 W than the I/I homozygotes. No associations were evident in Caucasian parents or Black parents or offspring. Thus, these data do not support the hypothesis that the I/I homozygotes of the ACE I/D polymorphism are more responsive to exercise training or that the ACE I/D polymorphism plays a major role in endurance performance. Supported by NIH

To estimate the association of age with maximal HR (MHR).Data were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were black and white men and women aged 18-30 yr in 1985-1986 (year 0). A symptom-limited maximal graded exercise test was completed at years 0, 7, and 20 by 4969, 2583, and 2870 participants, respectively. After exclusion, 9622 eligible tests remained.In all 9622 tests, estimated MHR (eMHR, bpm) had a quadratic relation to age in the age range of 18-50 yr, eMHR = 179 + 0.29 x age - 0.011 x age(2). The age-MHR association was approximately linear in the restricted age ranges of consecutive tests. In 2215 people who completed tests of both years 0 and 7 (age range = 18-37 yr), eMHR = 189 - 0.35 x age; and in 1574 people who completed tests of both years 7 and 20 (age range = 25-50 yr), eMHR = 199 - 0.63 x age. In the lowest baseline body mass index (BMI) quartile, the rate of decline was 0.24 bpm*yr(-1) between years 0 and 7 and 0.51 bpm*yr(-1) between years 7 and 20, whereas in the highest baseline BMI quartile, there was a linear rate of decline of approximately 0.7 bpm.yr for the full age range of 18-50 yr.Clinicians making exercise prescriptions should be aware that the loss of symptom-limited MHR is much slower in young adulthood and more pronounced in later adulthood. In particular, MHR loss is very slow in those with the lowest BMI younger than 40 yr.

Lortie, G.; Simoneau, J. A.; Boulay, M. R.; Hamel, P.; Thériault, G.; Bouchard, C. FACSM. Author Information

No abstract is provided for this article.

RICE, T., P. AN, J. GAGNON, A. S. LEON, J. S. SKINNER, J. H. WILMORE, C. BOUCHARD, and D. C. RAO. Heritability of HR and BP response to exercise training in the HERITAGE Family Study. Med. Sci. Sports Exerc., Vol. 34, No. 6, pp. 972–979, 2002. Purpose The heritability of the response to exercise training in resting blood pressure (BP) and heart rate (HR) was assessed in 482 Caucasian individuals comprising 98 families participating in the HERITAGE Family Study. Methods All individuals were sedentary at the baseline visit (time 1 measurement). After completing a 20-wk exercise-training program, subjects were measured again (time 2). A familial correlation model was used to assess the heritability (genetic plus familial environmental) of the response in resting systolic BP (SBP), diastolic BP (DBP), and HR, computed as the difference between the two measurement times. This response was adjusted for the effects of baseline levels and age within sex and generation groups. Analyses were conducted separately in a subsample of families in which at least one family member was considered to have elevated BP (95th percentile; SBP ≥ 135 or DBP ≥ 80). Results Several novel findings emerged from this study. First, the SBP and HR response may be influenced by genetic factors. The maximal heritabilities were 20% (SBP) and 36% (HR) in the elevated BP, 18% and 24% in the complete, and not significant in the normotensive samples. For DBP, there were cohort effects (significant sibling and spouse but not parent-offspring correlations) in the complete and normotensive samples that may be due to generation-specific environmental influences. Conclusion The trainability of SBP and HR in families with elevated BP appears to be determined in part by genetic factors, whereas DBP trainability may be more a function of environmental effects.

0709 The K+ voltage-gated channel of the shaker-related subfamily member 4 (KCNA4) gene (11p14), encodes for the K+ transient current (ito) channel which modulates the cardiac cell action potential. PURPOSE: We tested the hypothesis of an association between a C\T transition in the KCNA4 gene and OV2max response (Δ = Pre – Post OV2max) to 20-wk endurance-training (ET). METHODS: Pre- and Post-ET OV2max was measured by progressive exercise tests on a cycle ergometer. The polymorphism was detected by PCR and digestion with Tsp45I in 759 DNA samples from the HERITAGE Family Study (Blacks = 267 and Whites = 492). RESULTS: ÷2: ÷ indicated Hardy- Weinberg equilibrium and that the observed genotype frequencies were not different between races or genders. Δ values for OV2max adjusted for age, gender, race, Pre-ET OV2max, and body mass were characterized by genotype differences (P = 0.045). TT carriers had significantly lower ΔOV2max (396.4 ± 25 mL/min) than both CC (423.6 ± 25 mL/min) and CT carriers (435.6 ± 21 mL/min). CONCLUSIONS: The C/T transition at the KCNA4 locus or a gene in strong linkage disequilibrium is associated with ΔOV2max in Blacks and Whites. Supported by NHLBI of NIH, RCMI-CRC #1P20RR11126, and RCMI #G12RR03051.

The aim of this study was to investigate the association between a restriction fragment length polymorphism (RFLP) at the 3β‐hydroxysteroid dehydrogenase locus and adipose tissue distribution pheno‐types. A total of 132 unrelated individuals from the Quebec Family Study were followed prospectively for an average period of 11.3 years. The Bgl II polymorphism in exon 4 of the 3β‐HSD gene was detected by PCR. Body mass, body fat, and regional fat distribution indicators were adjusted for age and age 2 within each gender. Associations were assessed in unrelated adults with ANOVA across three genotypes. No association was found for the indicators of body mass, body fat, and regional distribution of adipose tissue measured in 1992. In women, the changes (difference between data collected in 1992 and at entry) in the sum of six skinfolds (p=0.04), abdominal skinfold (p=0.01), and abdominal skinfold adjusted (p=0.03) for the sum of six skinfolds at entry were related to the Bgl II polymorphism at the 3β‐HSD locus. These relations were not found in men, but they gained less body mass and body fat over the 11.3‐year period. This suggests that sequence variation at the 3β‐HSD locus or in neighboring genes on chromosome 1 may contribute to individual differences in body fat content and adipose tissue distribution in adult women, particularly in abdominal adipose tissue deposition as they grow older and gain body fat.

OBJECTIVE: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. We hypothesized that regular exercise has beneficial effects on the overall lipoprotein subclass profile in previously sedentary adults. METHODS: NMR spectroscopy (LipoScience Inc., Raleigh, NC) was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P respectively) before and after an exercise intervention in 1,430 adults from six studies, encompassing 10 exercise training groups: APOE (N=106), DREW (N=298), GERS (N=79), HERITAGE (N=715), STRRIDE I (N=130) and II (N=102). Random-effects meta-analysis was performed to quantify the overall mean change across the unadjusted and adjusted mean change estimates from each exercise group of each study. A Bonferroni-adjusted p-value ≤ 0.003 was considered statistically significant. RESULTS: Meta-analysis of unadjusted data found that regular exercise induced significant decreases in the concentration of large VLDL-P (P=1.2x10 -6 ) and mean VLDL-P size (P=9.0x10 -5 ), with significant increases in the concentration of large LDL-P (P=4.9x10 -13 ). The changes in large VLDL-P and large LDL-P concentration and VLDL-P size remained significant after adjustment for age, sex, race, baseline body mass index, and baseline trait value ( Figure 1 ); while the increase in LDL-P size (P=0.003) became significant after adjustment. Nominally significant decreases in the concentration of small LDL-P (P=0.004) and medium HDL-P (P=0.007) and increases in large HDL-P (P=0.008) were observed in the adjusted meta-analysis. CONCLUSIONS: Despite differences in exercise programs and study populations, regular exercise led to significant improvements in the lipoprotein subclass profile across 10 exercise interventions, as highlighted by changes in VLDL and LDL subfractions.

Background: Genes influencing resting metabolic rate (RMR) and respiratory quotient (RQ) represent candidate genes for obesity, type 2 diabetes, and the metabolic syndrome because of the involvement of these traits in energy balance and substrate oxidation. Objective: We conducted a genome-wide scan for quantitative trait loci (QTL) contributing to the variability in RMR and RQ. Design: Regression-based and variance components–based genome-wide autosomal scans on RMR and RQ phenotypes, obtained from indirect calorimetry, were performed in 169 families ascertained via an obese proband or from the general population. Results: We found evidence for linkage to RMR on chromosomes 3q26.1 (lod = 2.74), 1q21.2 (2.44), and 22q12.3 (1.33). QTL influencing RQ were found on chromosomes 12q13 (1.65) and 14q22 (1.83) when the analyses were performed in all families. Considerable locus heterogeneity within this population was suggested because most of the families were unlinked to any one quantitative trait locus. Significant associations between traits and linked microsatellites were detected within the linked, informative subsets. Conclusions: We found several new QTL for energy metabolism, but the QTL on 1q may be a replication of the one reported in Pima Indians. All 3 RMR linkages overlapped regions previously linked to the metabolic syndrome or its components, and the significant association between RMR and the metabolic syndrome in the present cohort reinforces this relation. We conclude that considerable locus heterogeneity exists even within populations, which should be taken into account when considering candidate gene studies of energy metabolism phenotypes and other complex traits.

Panel 5 focused on genetic factors that might mediate or moderate the effects of caloric restriction (CR) on longevity. Panel members stated that currently there is limited information directly addressing these issues. Therefore, they focused attention on what studies could be done. In addition, the panel believed that certain conceptual issues merited clarification and focused attention on this issue. Human studies and studies of nonhuman model organisms were discussed. The panel found at least three reasons why it would be valuable to find genes that influence the (putative) longevity-promoting effect of CR in humans. Such knowledge would offer: (a) the ability to predict individual responses to CR; (b) increased understanding of physiological mechanisms; and (c) the potential to develop mechanism-based interventions to promote longevity or healthy aging. In addition, the panel emphasized several macro-level recommendations regarding research strategies to avoid, research strategies to emphasize, and resources needing development.

Background: Glycine is a non-essential amino acid that has been inversely associated to coronary heart disease (CHD), with recent data suggesting that this relationship may be mediated by lower blo...