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ObjectivesWe investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.MethodsA total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%–75% of participants’ maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.ResultsOnly one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.ConclusionsInterindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.

The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study.

We investigated the associations between steroid hormones and resting and exercise blood pressure in the sedentary state and in response to an exercise program controlling for sex, body mass, ethnicity, age, oral contraceptives, hormone therapy, smoking and alcohol intake in subjects from the HERITAGE Family Study. In the sedentary state, 267 men (28% Blacks) and 301 women (37% Blacks) were available, and 241 men and 254 women completed the exercise program. Fourteen steroid hormones and sex hormone-binding globulin concentrations were assayed in a fasted state. Statistical significance was set at a Bonferroni adjusted p

Background and aims GlycA is a relatively new biomarker for inflammation as well as cardiometabolic disease risk. However, the effect of exercise on GlycA is largely unknown. Therefore, the purpose of this study was to examine the effects of regular exercise on the inflammatory marker GlycA across seven studies and 14 exercise interventions. Methods Nuclear magnetic resonance spectroscopy, specifically signal amplitudes originating from the N-acetyl methyl group protons of the N-acetylglucosamine residues on the glycan branches of glycoproteins, was used to quantify GlycA concentrations. GlycA was measured before and after completion of an exercise intervention in 1568 individuals across seven studies and 14 exercise interventions. Random effects inverse variance weighting models were used to pool effects across interventions. Results Combined analysis of unadjusted data showed that regular exercise significantly (p = 2 × 10−6) reduced plasma GlycA (−8.26 ± 1.8 μmol/L). This reduction remained significant (−9.12 ± 1.9 μmol/L, p = 1.22 × 10−6) following adjustment for age, sex, race, baseline BMI, and baseline GlycA. Changes in GlycA were correlated with changes in traditional inflammatory markers, C-reactive protein, interleukin-6, and fibrinogen, however, these correlations were relatively weak (range r: 0.21–0.38, p Conclusions Regular exercise significantly reduced plasma GlycA across 14 different exercise interventions despite differences in exercise programs and study populations. The current study provides a greater understanding of the use of exercise as a potential therapy for the reduction of systemic inflammation. Further research is needed to understand the mechanisms behind the exercise-related reductions in GlycA.

Plasma steroid hormone levels vary between men and women, but their associations with BMI and adiposity are controversial. Furthermore, little is known about the role of exercise programs on the relationship between steroid hormones and adiposity. This report evaluates these relationships for plasma levels of adrenal, gonadal, and conjugated steroids with body composition and fat distribution in sedentary men and women, aged 17–65 years, and their responses to an exercise program. In the sedentary state, 270 men (29% Blacks) and 304 women (34% Blacks) from the HERITAGE Family Study were available. Among them, 242 men and 238 women completed a 20-week fully standardized exercise program. Fourteen steroid hormones and SHBG concentrations were assayed in a fasted state and were compared for their associations with adiposity in men and women and in response to the exercise program. Covariates adjusted for in partial correlation analysis were age, ancestry, menopause status (women), and oral contraceptives/hormone replacement treatment status (women) at baseline, as well as baseline value of the trait for the training response. Differences among normal weight, overweight, and obese subjects were also considered. Statistical significance was set at P

Background: Older adults with Alzheimer’s disease (AD) may be unable to perform treadmill testing due to balance issues. We investigated whether older adults with AD could successfully complete a peak cycle ergometer test. Methods: Peak oxygen consumption (peak [Formula: see text]) assessed via a cycle ergometer test in 44 participants with AD (age 78.4 ± 6.8). Physical function was assessed via the incremental shuttle walk, 6-minute walk, and the Short Physical Performance Battery (SPPB). Results: All participants completed the cycle ergometer test successfully. Peak [Formula: see text] was correlated with SPPB ( r = .35, P = .023), shuttle walk ( r = .35, P = .024), 6-minute walk ( r = .31, P = .05), and inversely with age ( r = −.4, P = .009). There was no correlation between peak [Formula: see text] and cognition. Conclusion: Older adults with AD are able to safely complete a peak cycle ergometer exercise testing protocol. We provide an individualized cycle ergometer test for determining aerobic capacity in older adults with AD who may be unable to perform treadmill testing due to balance or gait issues.

Objective The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. Methods Nuclear magnetic resonance spectroscopy 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 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. Results Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value. Conclusions Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise-induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk.

Objective Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. Methods Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. Results In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. Conclusions In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism., Graphical abstract, Highlights • In male humans, plasma adropin concentrations are inversely related to low-density circulating cholesterol (LDL-C) levels. • Adropin expression is regulated by core elements of the biological clock (RORA/G, Rev-Erb). • Sterol-sensing by the ROR ligand-binding domain provides a plausible link between adropin expression and lipid metabolism. • In mouse liver, adropin expression is rhythmic and suppressed by exogenous (dietary) cholesterol.

Objective The purpose of this study was to examine how well two commonly used age-based prediction equations for maximal heart rate (HRmax) estimate the actual HRmax measured in Black and White adults from the HERITAGE Family Study. Methods A total of 762 sedentary subjects (39% Black, 57% Females) from HERITAGE were included. HRmax was measured during maximal exercise tests using cycle ergometers. Age-based HRmax was predicted using the Fox (220-age) and Tanaka (208 – 0.7 × age) formulas. Results The standard error of estimate (SEE) of predicted HRmax was 12.4 and 11.4 bpm for the Fox and Tanaka formulas, respectively, indicating a wide-spread of measured-HRmax values are compared to their age-predicted values. The SEE (shown as Fox/Tanaka) was higher in Blacks (14.4/13.1 bpm) and Males (12.6/11.7 bpm) compared to Whites (11.0/10.2 bpm) and Females (12.3/11.2 bpm) for both formulas. The SEE was higher in subjects above the BMI median (12.8/11.9 bpm) and below the fitness median (13.4/12.4 bpm) when compared to those below the BMI median (12.2/11.0 bpm) and above the fitness median (11.4/10.3) for both formulas. Conclusion Our findings show that based on the SEE, the prevailing age-based estimated HRmax equations do not precisely predict an individual's measured-HRmax. Am. J. Hum. Biol., 25:695–701, 2013. © 2013 Wiley Periodicals, Inc.

The aim of this report is to evaluate the relationships between baseline levels of adrenal, gonadal and conjugated steroids and baseline cardiorespiratory fitness, as assessed by maximal oxygen uptake (VO2max), as well as its response to a standardized exercise program. To address this aim we used a subset of the HERITAGE Family Study (N = 448). In men, significant positive associations were found between baseline VO2max/kg weight and plasma levels of androsterone glucuronide (ADTG), dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone binding globulin (SHBG), and testosterone (TESTO), and negative association with aldosterone (ALDO). In women, only the free androgen index (FAI) was negatively associated with baseline VO2max/kg weight. Neither baseline plasma steroid levels nor SHBG concentrations were associated with the gains in VO2max resulting from exposure to the 20-week aerobic exercise program after adjustment for baseline values, age and ethnicity (white or black). We conclude that baseline plasma steroid levels are only weakly associated with individual differences in cardiorespiratory fitness in the sedentary state in men but not in women, whereas no association could be detected with trainability, as defined by the change in VO2max with the exercise program.

Beginning early in midlife, natural/primary aging is inevitably associated with a progressive reduction in muscle mass and function. This process can progress with aging to a substantial loss of strength, particularly in the lower extremities, reducing mobility. This condition, commonly referred to as sarcopenia, can result in frailty, reducing one’s ability to live independently. This article reviews the underlying biological process contributing to the development of sarcopenia and the roles of regular exercise and nutritional support for attenuating aging-associated muscle loss as well as risk and management of sarcopenia and associated frailty.

Psoriasis is a common, chronic inflammatory skin disease that can cause significant discomfort and impairment to quality of life. Recent research indicates that individuals with moderate-to-severe psoriasis are likely at greater risk for chronic cardiometabolic co-morbidities such as cardiovascular disease, type 2 diabetes, obesity and metabolic syndrome. Physical activity can be an effective primary and adjunctive treatment for these maladies in other populations. Unfortunately, only a limited number of studies have examined physical activity in psoriasis, which are limited by poor design and lack of validated physical activity assessment methodologies. A variety of data suggest shared physiologic pathways between physical activity, psoriasis, and psoriasis cardiometabolic co-morbidities. Increased adiposity, inflammation, oxidative stress, adhesion molecules and lipids are physiologically linked to psoriasis, the risk of psoriasis cardiometabolic co-morbidities, and low levels of physical activity. In addition, epigenetic pathways are involved in psoriasis and could be influenced by physical activity. The physical and psychosocial impairments common in psoriasis may make it difficult to participate in regular physical activity, and future studies should aim to determine if physical activity interventions improve functioning and reduce co-morbidities in psoriasis.

Following physical maturity, all body functions inevitably progressively decline with aging; however, there is a great deal of variability in the rate of decline and the associated development of significant functional impairments. Both genetic and lifestyle factors, including physical activity habits, contribute to this variability in physiological changes, as well as to the associated risk of chronic degenerative diseases. The effect of healthy natural aging on functional capacity and its related cardiovascular and respiratory contributors has primarily been studied by cross-sectional and, less frequently, by longitudinal studies. In these studies, physically active men and women at all ages were observed to have a superior functional capacity, as well as a lower rate of cardiovascular disease morbidity and mortality, as compared with matched sedentary individuals. In addition, a limited number of studies, involving healthy elderly men and women, have demonstrated that moderate-to-vigorous exercise training can substantially improve functional capacity and modify many of the age-related cardiovascular changes. The purpose of this article is to review the effects of natural or so-called primary or eugeric aging on the cardiovascular system and associated functional capacity and the extent of modification of these changes by regular exercise.

Little is known about cardiorespiratory fitness and aerobic exercise training in older adults with Alzheimer’s disease (AD). The purposes of this article are to describe the change in cardiorespiratory fitness after 2 months of aerobic training and the feasibility of aerobic training in 4 men with moderate-to-severe AD. A one-group, pretest-posttest test design was used to measure cardiorespiratory fitness using symptom limited, graded cycle ergometer testing. In exit interviews, participants and spouses identified exercise facilitators and barriers. The results show that cardiorespiratory fitness increased in 2 participants with moderate AD but decreased in 2 with severe AD. Participants showed great variability in exercise progression and doses actually delivered. In conclusion, older men with moderate-to-severe AD can engage in aerobic training. Two months might be better used as the adaptive period for longer duration aerobic training, such as a 6-month program. Suggestions and implications for future exercise research in AD are detailed.

Background Ischemia-induced pain associated with walking (claudication) in peripheral artery disease limits mobility and diminishes quality of life. Self-reports of pain during standardized treadmill testing are used in clinical trials to assess the efficacy of interventions. Objectives The aim of this study was to model pain trajectories during a peak walking test after 12 weeks of treatment in participants in four randomly assigned treatment groups (treadmill, arm ergometry, combination, and usual care) compared with baseline pain trajectories. Methods Self-reports of pain obtained at baseline and after 12 weeks of supervised exercise training for 41 participants (71% male; age, M = 64 years, SD = 8.6 years) were used. Pain was measured every 30 seconds with a numeric rating scale that had ordinal response options ranging from 0 (no pain) to 5 (severe pain). The test was continued until the maximum level of pain was reached and the participant could no longer walk. Observed responses from individual cases were plotted and patterns of pain were identified. A hierarchical generalized linear model for ordinal data was fit to compare baseline and postintervention trajectories. Results : Patterns in observed data reflected variations in time to onset of mild pain, acceleration to severe pain, and total walking time. All groups improved at 12 weeks; arm ergometry trajectories showed slower onset of pain, whereas treadmill training produced slower rates of increase to the maximum toward the end of the test. Effects for individuals appear as offsets from personal models at baseline. Discussion Change in the experienced claudication trajectory varied by type of exercise. Findings can inform design of future trials and aid decision making about exercise interventions for claudication.

Atherosclerosis, the underlying cause of coronary heart disease (CHD), is a chronic inflammatory condition involving the subendothelial layer of coronary as well as other large-and medium-sized arteries. This disease process is initiated early in life by multiple risk factors. Endothelial dysfunction and lipid infiltration are fundamental for the initiation and progression of the atherosclerotic process. After many asymptomatic decades, acute coronary syndromes are generally triggered by a coronary occlusion, caused by a thrombosis initiated by disruption of a vulnerable lipid-laden plaque with a thin, noncalcified fibrosis cap. Epidemiology studies over the past 50 years have consistently observed an inverse association between CHD and regular physical activity and/or cardiorespiratory fitness. Supporting evidence of causative relationships has been provided by exercise training studies demonstrating multiple, plausible, cardioprotective, biological mechanisms. These pleotropic effects may be classified as (1) direct antiatherosclerotic effects and indirect effects via reduction of other risk factors, (2) anti-ischemic effects by decreasing myocardial oxygen demands and increasing its vascular supply and by decreasing the severity of ischemic injuries by direct conditioning effects on cardiomyocytes, (3) antiarrhythmic effects by improving electrical stability of the heart, and (4) antithrombotic (and prothrombolytic) effects, reducing risk of a coronary thrombotic occlusion. It is concluded based on an impressive body of evidence that regular aerobic exercise attenuates the risk of CHD at all stages of the atherothrombotic process.

Multiple risk factors have a causative relationship to the etiology of coronary heart disease (CHD). However, it is clear that dyslipidemia plays a central role. The chain of evidence is strongest for elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). An inverse association has also been demonstrated between levels of high-density lipoprotein cholesterol (HDL-C) and its principal apolipoprotein, A-1, and risk of CHD. Elevated levels of fasting triglyceride (TG) also are a predictor of CHD, but the independent contribution of TG is difficult to prove because of its usual association with reduced levels of HDL-C; elevated levels of small, dense, highly-atherogenic LDL particles; and the metabolic syndrome. Elevated fasting levels of non—HDL-C (TC — LDL-C) and apolipoprotein B also are strongly predictive of the risk of CHD. Therapeutic lifestyle changes are important adjuncts to pharmacologic management of dyslipidemia. The purpose of this article is to review these contributions with an emphasis on dietary habits (particularly lipid intake), weight management, and aerobic exercise.

Objective: Our goal was to examine the effects of regular endurance exercise on plasma GlycA levels, a novel NMR-derived biomarker of systemic inflammation. Methods: We examined NMR-derived plasma GlycA levels before and after 5-6 months of exercise training in 1,194 adults from four studies: APOE (N=104), DREW (N=298), GERS (N=78), HERITAGE (N=714). We used unadjusted and adjusted general linear models to evaluate changes in GlycA with regular exercise across sex-specific quartiles of baseline GlycA in all studies combined. Results: At baseline, the combined participants (69% white, 66% female) were an average of 42.5 (15.4) years old with a mean BMI of 28.1 (5.8) kg/m 2 . Exercise training resulted in a decrease in GlycA of 5.6 (42.0) μmol/L (PFigure 1 ). In both models, Q4 showed the greatest decrease in GlycA. Conclusions: Regular exercise tended to decrease GlycA levels across four diverse, standardized exercise training studies. Our results suggest that the individuals at highest risk appear to benefit the most from regular exercise in terms of GlycA. Figure 1. Mean change in GlycA after exercise training by baseline GlycA quartile in four exercise studies combined . P2 max, baseline GlycA quartile, and three study group dummy variables as covariates. Sex-specific baseline GlycA quartiles in combined group (M/F): Q1: 370/>395

Contributions of the DNA sequence variation at the endothelin 1 locus to the risk of hypertension and to endurance training–induced changes in blood pressure were investigated in the Aerobics Center Longitudinal Study and the Health, Risk Factors, Exercise Training and Genetics Family Study cohorts. We identified 586 normotensive control subjects and 607 incident hypertensive case subjects from the Aerobics Center Longitudinal Study cohort (all whites) who were normotensive and healthy at their first clinic visit. The case subjects were diagnosed with hypertension during an average follow-up of 9.5 years, whereas the control subjects remained normotensive. The allele and genotype frequencies of 5 endothelin 1 haplotype tagging single nucleotide polymorphisms did not differ significantly between the case and control subjects. However, we observed a significant ( P =0.0025) interaction between the endothelin 1 rs5370 (G/T; Lys198Asn) genotype and cardiorespiratory fitness level on the risk of hypertension: among low-fit subjects, the rs5370 minor allele (T; 198Asn) was associated with higher risk of hypertension (odds ratio: 1.95; 95% CI: 1.36 to 2.81; P =0.0003), whereas the risk did not differ among genotypes in high-fit subjects. In the white Health, Risk Factors, Exercise Training and Genetics subjects (N=480), the rs5370 T allele was associated with blunted systolic blood pressure ( P =0.0046) and pulse pressure ( P =0.0016) responses to a 20-week endurance training program. The Lys198Asn variant of the endothelin 1 locus is associated with blood pressure phenotypes in whites. However, the expression of the genotype effect is modulated by physical activity or cardiorespiratory fitness level. Our study provides an illustrative example of how physical activity and fitness level modifies the associations between a candidate gene and outcome phenotype.

Associations between cholesteryl ester transfer protein (CETP) polymorphisms and high-density lipoprotein cholesterol (HDL-c) levels before and after 20 wk of endurance training were investigated in the HERITAGE Family Study. Plasma HDL-c, HDL2-c, HDL3-c, and apolipoprotein (apo)A1 levels were measured, and 13 CETP single nucleotide polymorphisms (SNPs) were genotyped in 265 blacks and 486 whites. Three haplotypes defined by SNPs at the −1337, −971, and −629 sites were strongly associated with baseline HDL-c levels in whites. Both C−1337T and C−629A were associated with baseline HDL-c ( P < 0.001) and apoA1 ( P < 0.01) when tested separately. However, only C−629A remained significant in a combined model. G−971A was not associated with HDL phenotypes, but showed significant interactions with C−629A ( P = 0.002) on baseline traits. Genotype-by-sex interactions were observed at the −629 locus for HDL3-c ( P = 0.004) and apoA1 ( P = 0.02) training responses in whites. In women, the −629 A/A homozygotes showed greater increases in HDL3-c ( P = 0.02) and apoA1 ( P = 0.02) levels than the other genotypes. Finally, apolipoprotein E (APOE) genotype and the CETP C−629A locus contributed independently and in additive fashion to the HDL traits, explaining 6.0–8.8% of the variance. The CETP −1337T and −629A alleles are associated with higher baseline HDL-c and apoA1 levels. The beneficial effects of endurance training on plasma HDL3-c and apoA1 levels are evident in white women homozygous for the −629A allele. The CETP and APOE genotypes account for up to 9% of the variance in HDL-c phenotypes in the HERITAGE Family Study.

We tested the hypothesis that peroxisome proliferator-activated receptor-δ (PPARδ) gene polymorphisms are associated with cardiorespiratory fitness and plasma lipid responses to endurance training. Associations between the PPARδ exon 4 +15 C/T and exon 7 +65 A/G polymorphisms and maximal exercise capacity and plasma lipid responses to 20 wk of endurance training were investigated in healthy white ( n = 477) and black ( n = 264) subjects. In black subjects, the exon 4 +15 C/C homozygotes showed a smaller training-induced increase in maximal oxygen consumption ( P = 0.028) than the C/T and T/T genotypes. Similarly, a lower training response in maximal power output was observed in the exon 4 +15 C/C homozygotes ( P = 0.005) compared with the heterozygotes and the T/T homozygotes in black subjects, and a similar trend was evident in white subjects ( P = 0.087). In white subjects, baseline apolipoprotein A-1 (Apo A-1)levels were higher in the exon 4 +15 C/C ( P = 0.011) and exon 7 +65 G/G ( P = 0.05) genotypes compared with those in the other genotypes. In white subjects, exon 4 +15 C/C ( P = 0.0025) and exon 7 +65 G/G ( P = 0.011) genotypes showed significantly greater increases in plasma high-density lipoprotein-cholesterol (HDL-C) levels with endurance training than in the other genotypes, whereas in black subjects the exon 4 +15 CC homozygotes tended to increase ( P = 0.057) their Apo A-1 levels more than the T allele carriers. DNA sequence variation in the PPARδ locus is a potential modifier of changes in cardiorespiratory fitness and plasma HDL-C in healthy individuals in response to regular exercise.

Exercise conditioning of young male rats by swimming for 1 h, 5 times per week for 10 weeks results in a reduced gain in body weight, cardiac hypertrophy and hyperplasia, an increase in myocardial capillary density, and an increase in cross-sectional laminal areas of extracoronary collateral arteries. The effects of partial or complete deconditioning on these changes were studied by randomizing young male rats exercise-conditioned for 10 weeks to groups either kept sedentary or subjected to varying amounts of exercise for a second 10-week period. Their hearts were compared with those of unexercised controls using quantitative histologic measurements. During the second 10 weeks, exercise conditioning was found not to continue to suppress weight gain. However, frequent relative short-duration exercise sessions (as little as 15 min per session) frequently prevented an accelerated increase in body weight associated with deconditioning. A complete regression of exercise-induced cardiovascular adaptive changes occurred when wxercise was discontinued completely for 10 weeks or the duration of sessions was cut to 15 min. In order to maintain cardiac hypertrophy, exercise had to be continued for 1 h, 5 times per week while hyperplasia could be maintained with shorter duration, less frequent sessions (30 min, twice a week). The maintenance of increased myocardial capillary density required a similar amount of exercise, and at least 1 h of exercise once a week was necessary to maintain the enlargement of ECA.20

C-reactive protein (CRP) is a sensitive marker of systemic low-grade inflammation. Increased plasma levels of CRP predict the risk of cardiovascular and metabolic diseases. Although genetic factors account for 30–40% of individual differences in plasma CRP levels, genomic regions contributing to CRP levels remain unknown. We performed a genome-wide linkage scan for plasma CRP levels in healthy whites from the HERITAGE Family Study. CRP was measured with a high-sensitivity assay. Multipoint linkage analyses were performed in 280 sibling pairs with 654 markers using regression and variance components-based methods. Data were adjusted for independent correlates of plasma CRP. We showed the strongest evidence of linkage for plasma CRP levels on chromosome 20q13. Markers which gave suggestive linkages in this region were D20S52 [logarithm of odds (LOD) score 3.18, P = 0.00006], D20S857 (LOD score 2.87, P = 0.00014), D20S869 (LOD score 2.75, P = 0.0002), D20S480 (LOD score 2.59, P = 0.0003), D20S501 (LOD score 2.55, P = 0.0003), D20S840 (LOD score 2.18, P = 0.0008), and D20S876 (LOD score 2.07, P = 0.001). We also detected suggestive linkage on chromosome 5p13 for marker D5S1470 (LOD score 2.23, P = 0.0007). Chromosome 20q13 may contribute to plasma CRP levels in healthy whites. This region contains genes that are important in the inflammatory process and may play a role in the development of chronic inflammatory diseases. The present findings may be useful in the ongoing effort to search for genes contributing to inflammation and to identify individuals at an increased risk of chronic inflammatory diseases.

Background The purpose of the present study was to compare endothelial function in lean (body mass index [BMI] = 18.0–24.9 kg/m2); overweight (BMI = 25–29.9 kg/m2); and obese (BMI > 30 kg/m2), healthy, eumenorrheic women. Methods Eighteen lean, 22 overweight, and 19 obese eumenorrheic middle-aged women were studied. Vascular structure and function were assessed via non-invasive ultrasound imaging of the carotid and brachial arteries. Body composition, blood pressure, fasting blood lipids, glucose, and insulin also were measured. Results The groups demonstrated significantly (p Conclusions The results of this study support the hypothesis that carotid artery wall cross-sectional area is elevated and flow-mediated dilation reduced in overweight and obese eumennorheic women as compared to lean counterparts in relation to BMI classification.

Objective Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), stimulate the release of C-reactive protein (CRP). We investigated the association between the TNF-α G-308A polymorphism and plasma CRP levels. Methods Subjects were 456 White (225 men, 231 women) and 232 Black (83 men, 149 women) healthy adults who underwent a 20-week standardized exercise program in the HERITAGE Family Study. The TNF-α gene promoter polymorphism was determined using PCR amplification followed by NcoI digestion. Plasma CRP was measured using a high-sensitivity assay. Results Genotype frequencies were in Hardy–Weinberg equilibrium. After adjustment for age, smoking, alcohol consumption, maximal oxygen uptake and, in women, hormone use, the AA homozygotes for the G-308A polymorphism had higher baseline CRP levels than other genotypes in White and Black men ( P P = 0.044, respectively) and in Black women ( P = 0.032). Body mass index partly explained these associations in Blacks. The exercise program results provided further evidence for an association with the polymorphism. Among those with high CRP at baseline (≥ 3.0 mg/L), regular exercise decreased CRP less in AA homozygotes than in other genotypes ( P = 0.043). Conclusion The AA genotype of the TNF-α G-308A polymorphism is associated with higher plasma CRP levels and less favorable CRP response to regular exercise.

Motivated by strong correlations between plasma levels of triglycerides (TG) and adiposity traits, we conducted a series of bivariate genome-wide linkage analyses of TG with body mass index (BMI), total fat mass (FAT), percentage of body fat (FATPC), and abdominal subcutaneous fat (ASF). Maximum lod scores of 3.3, 3.0, 2.2 and 2.4, respectively, were found on chromosome 19q13. This linkage region includes the APOE gene, a predictor of variation in lipid-lipoprotein levels, and the hormone-sensitive lipase (LIPE) gene, a key enzyme in the mobilization of fatty acids from triglyceride stores. In addition, the adiposity measures together with the APOE marker showed significant association with TG levels (p = 0.02 to p = 0.03). In summary, these results suggest that one or more QTLs in the 19q13 region jointly influence TG levels and adiposity. Polymorphisms in the APOE gene, and possibly LIPE gene, appear to be strong candidates for the source of this pleiotropic QTL.

Fasting triglyceride (TG) levels in total plasma and in lipoprotein subfractions were assessed both at baseline and after a 20-week exercise training intervention in 99 White and 101 Black families. A genome-wide multipoint variance component linkage analysis was performed separately by race, using 509 markers. The strongest evidence of linkage was for the TG subfractions of low-density lipoprotein (LDL-TG) and high-density lipoprotein (HDL-TG) rather than for overall levels of TG. For baseline levels, the maximum LOD score was 3.8 on 13q12-q14 with HDL-TG in Whites. Additional linkage evidence was found on 14q31 (LOD=3.2) and 10p14 (LOD=2.9) for baseline LDL-TG in Whites. Suggestive linkage signal at baseline in Whites was detected for HDL-TG (LOD=2.6) on 12q24 and for LDL-TG on 19p13. For training response in Whites, suggestive signal (LOD=2.2) was observed on 13q12-q14 with LDL-TG and for HDL-TG on 10q23. For Blacks, weak signals (LODs2.0) were found either for baseline and responses to training, perhaps due to small sample sizes that reduced the power of the linkage analysis. These results represent the first report of linkage for the lipoprotein subfractions and for the lipid and lipoprotein responses to exercise training. It is interesting that the strongest signals were found for the LDL-TG and HDL-TG subfractions, given their particular relationships with the atherogenic lipid profile including dense LDL and HDL particles.

We investigated the associations between the hepatic lipase gene (LIPC) −514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and post–exercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n = 662). The LIPC −514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and post–exercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low post–exercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 μU · min−1 · ml−1) than in the TT genotype (+0.27 ± 0.3 and −0.97 ± 0.3 μU · min−1 · ml−1) (P = 0.008 and P = 0.002, respectively). The LIPC −514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better Si responses to regular exercise both in black and white individuals. The benefits from an exercise program on Si are likely to be substantial in the general population given the high frequency of the LIPC −514C allele, particularly in whites.

Protein tyrosine phosphatase 1B (PTPN1) affects the regulation of insulin signaling and energy metabolism. We studied whether polymorphisms in the PTPN1 gene impact body fat distribution in the HERITAGE Family Study cohort in 502 white and 276 black subjects. Insulin sensitivity index, glucose disappearance index, acute insulin response to glucose (AIR(glucose)), and the disposition index (DI) were obtained from the frequently sampled intravenous glucose tolerance test. White subjects with the G82G at the PTPN1 IVS6+G82A polymorphism had higher body fat levels (p = 0.031) and sum of eight skinfolds (p = 0.003) and highest subcutaneous fat on the limbs (p = 0.002). G82A subjects had the lowest AIR(glucose) (p = 0.005) and disposition index (p = 0.040). Interaction effects between PTPN1 and leptin receptor gene variants influenced insulin sensitivity index and AIR(glucose) (p from 0.006 to 0.010). The variant PTPN1 Pro387Leu was associated with lower fasting insulin level (p = 0.035) and glucose disappearance index (p = 0.038). In summary, PTPN1 IVS6+G82G homozygotes showed higher levels of all measures of adiposity. G82 allele heterozygotes are potentially at higher risk for type 2 diabetes. Gene-gene interactions between the PTPN1 and leptin receptor genes contributed to the phenotypic variability of insulin sensitivity. The PTPN1 Pro387Leu variant was associated with lower glucose tolerance.

Adiponectin is an adipocytokine with lowered blood levels in obesity and Type 2 diabetes mellitus. We sought to define the specific effects of different alleles of the gene encoding adiponectin.We studied the associations of adiponectin gene sequence variations with body fat distribution and insulin indices in 503 White and 276 Black subjects of the HERITAGE Family Study cohort and subjects from a Finnish population.The His111 allele frequency of the Tyr111 His polymorphism in Finnish Type 2 diabetic subjects (n=254) was higher (5.1%) than in control subjects (n=270) (2.6%; P = 0.033). In the HERITAGE cohort, the His111 allele was associated with a lower insulin sensitivity index (P = 0.018) and a higher acute insulin response to glucose (P = 0.0098) in Whites. Other variants showed associations with adiposity and plasma lipid values only in Blacks. Among Blacks, the IVS2+G62T variant was associated with body fat (P = 0.002) and total cholesterol values (P = 0.005), and the Gly15Gly variant with cholesterol (P = 0.009) and triglyceride (P = 0.05) levels. The haplotype derived from these two polymorphisms was associated with total body fat, while the IVS2+G62T and Tyr111His-haplotype was associated with body fat and disposition index.The carriers of the His111 allele may have a higher risk of developing Type 2 diabetes mellitus. Racial differences were found between Blacks and Whites in body composition and lipids according to ACDC genotypes. Sequence variants in the adiponectin gene appear to be associated with diabetes and diabetes-related phenotypes.

Genome-wide multipoint linkage analyses were performed to identify chromosomal regions harboring genes influencing LDL-cholesterol, total apolipoprotein B (apoB), and LDL-apoB levels using 654 markers. They were assessed in a sedentary state (baseline) and after a 20 week endurance training program. Strong evidence for two quantitative trait loci (QTLs) for baseline levels was found. There is linkage evidence in black families on chromosomes 1q41-q44 [at marker D1S2860, 238 centimorgan (cM), with a maximum log of the odds (LOD) score of 3.7 for LDL-apoB] and in white families on chromosome 8q24 (at marker D8S1774, 142 cM, with LOD scores of 3.6, 3.3, and 2.5 for baseline LDL-cholesterol, LDL-apoB, and apoB, respectively). There were no strong signals for the lipoprotein training responses (as computed as the difference in posttraining minus baseline levels). In conclusion, QTLs for baseline apoB and LDL-cholesterol levels on chromosomes 1q41-q44 (in blacks) and 8q24 (in whites) were found. As there are no known strong candidate genes in these regions for lipids, follow-up studies to determine the source of those signals are needed.

Objective: Despite the well known genetic component influencing plasma lipid-lipoprotein levels and the observed correlations among these traits, little is known about pleiotropic heritable determinants among them. Our aim is to investigate pair-wise polygenic and environmental correlations among lipid-lipoprotein levels at baseline and in response to regular exercise in Whites and Blacks. Methods: Common pair-wise genetic and environmental correlations among levels of total cholesterol (TC), LDL-C, ApoB, HDL-C (also HDL2-C and HDL3-C), triglycerides (TG, HDL-TG and LDL-TG) and ApoA-1 were investigated at baseline and again after a 20-week endurance exercise program using a variance-components-decomposition. Results: With a few exceptions, all lipid phenotypes were heritable at baseline and for training responses in Blacks and Whites. Strong to high genetic and environmental correlations (0.4 < ρg < 0.7) were observed for the majority of the baseline pair-wise traits. For training responses, many of the same patterns were noted, although fewer genetic correlations were significant as compared to the baseline results. Conclusions: Results suggest that the observed phenotypic correlations among many of these traits may be due to in part to pleiotropic genes, in particular between LDL-C and ApoB and between TG and HDL-C. This shared genetic architecture should be considered in follow-up gene finding studies.

OBJECTIVE—To determine the effect of a 20-week endurance training program in healthy, previously sedentary participants on measures derived from an intravenous glucose tolerance test (IVGTT). RESEARCH DESIGN AND METHODS—An IVGTT was performed before and after a standardized training program in 316 women and 280 men (173 blacks and 423 whites). Participants exercised on cycle ergometers 3 days per week for 60 sessions. The exercise intensity was progressively increased from 55% Vo2max for 30 min per session to 75% Vo2max for 50 min per session. RESULTS—Mean insulin sensitivity increased by 10% (P < 0.001) following the intervention, but the variability in the changes was high. Men had larger improvements than women (P = 0.02). Improvements in fasting insulin were transitory, disappearing 72 h after the last bout of exercise. There were also significant mean increases in the glucose disappearance index (3%, P = 0.02) and in glucose effectiveness (11%, P < 0.001), measures of glucose tolerance and of the capacity of glucose to mediate its own disposal, respectively. The acute insulin response to glucose, a measure of insulin secretion, increased by 7% in the quartile with the lowest baseline glucose tolerance and decreased by 14% in the quartile with the highest baseline glucose tolerance (P < 0.001). The glucose area below fasting levels during the IVGTT was reduced by 7% (P = 0.02). CONCLUSIONS—Although the effects of structured regular exercise were highly variable, there were improvements in virtually all IVGTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis.

The purpose of this research was to investigate the effects of apriori estrogen replacement therapy (ERT) and endurance exercise training in postmenopausal women on abdominal visceral fat (AFV) and other selected variables related to body composition and the metabolic syndrome (MS). Forty-eight healthy and previously sedentary postmenopausal women (mean age, 54.3 years) who were enrolled in the HERITAGE Family Study (HFS) served as subjects. Of these 48 women, 18 were currently taking ERT and the remaining 30 were taking no supplemental estrogen (NHRT). Computed tomography (CT) scans were used to assess AVF as well as total abdominal fat (TAF) and abdominal subcutaneous fat (ASF). Body mass index (BMI) and waist-to-hip ratios (WHR) were calculated while body fat percentage (%FAT) and total fat mass (FATM) was assessed using underwater weighing. Blood assays for HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG) were conducted at a Centers for Disease Control (CDC) certified laboratory, while blood pressure measurements were assessed using an automated system. All measurements were obtained in duplicate before and after a regimen of endurance exercise training. Analysis of variance (ANOVA) showed AVF to be an average of 31.6 cm(2) less in the women receiving ERT, but lost statistical significance when AVF was adjusted for FATM. Mean values for TAF, ASF, and waist girth were also less in the women receiving ERT, but only waist girth achieved statistical significance. No differences were found in BMI or %FAT, but mean WHR was 5% smaller in the ERT group. Baseline values for HDL-C was higher and LDL-C lower in the ERT group. Prevalence of the MS tended to be greater in the NHRT group, but did not achieve statistical significance. There were no differences in training responses in any of the body composition variables between groups, however, in the ERT group LDL-C decreased with training while TG increased. It was concluded that postmenopausal women taking ERT tended to have lower values of AVF and other indicators of body composition, a more favorable lipid profile, and a slightly reduced risk of the MS when compared with women not taking supplemental hormones. Also exercise training did not improve the overall MS status of either group, as LDL-C status improved in the ERT group while TG decreased in the NHRT group.

PURPOSE This study explores sex and race differences in the association between changes in fat mass (FM), abdominal visceral fat (AVF), and abdominal subcutaneous fat (ASF) on blood lipid changes consequent to aerobic exercise training. METHODS The sample included 613 participants (428 white and 185 black, 46% men) from the HERITAGE Family Study. Total FM was determined by densitometry, whereas AVF and ASF cross-sectional areas were determined by computed tomography at the L4-L5 level. Blood lipid measurements included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the TC/HDL-C ratio, which were obtained before and after 20 wk of supervised aerobic exercise. Canonical correlation was used to determine the multivariate associations between body fatness and blood lipids at baseline and the changes induced by exercise training. RESULTS Body fat accounted for 26-36% of the variance in baseline blood lipids, and changes in body fat accounted for 7-21% of the variance in changes in blood lipids with exercise training. The pattern of loadings indicated similar relationships between body fatness and blood lipids at baseline, and their respective changes with exercise training among the four sex-by-race groups. Greater fat loss, characterized by loss of FM, AVF, and ASF, was associated with a greater blood lipid response characterized by an increase in HDL-C and decreases in LDL-C, TG, TC, and TC/HDL-C. Although the pattern of loadings was similar in all groups, the strength of the association was stronger in blacks than in whites. CONCLUSION The multivariate associations among fat loss and changes in blood lipids consequent to aerobic exercise training are similar in black and white men and women.

Calcium (Ca(2+)) intake may play a role in the regulation of body weight. Increased Ca(2+) intake has been associated with lower body weight, BMI, and adiposity measures in cross-sectional studies. We examined the association between Ca(2+) intake, derived from the Willett FFQ, and overall and abdominal adiposity in Black and White men and women of the HERITAGE Family Study. BMI, the percentage of body fat (%FAT), the sum of 8 skinfold thicknesses, computerized tomography total abdominal fat (TAF), abdominal visceral (AVF) and abdominal subcutaneous (ASF) fat, and waist circumference were measured in 362 men (109 Blacks, 253 Whites) and 462 women (201 Blacks, 261 Whites). Subjects were divided into tertiles of energy-adjusted Ca(2+) intake. Adiposity measures across tertiles were compared by ANOVA and also regressed against the energy-adjusted Ca(2+) intake to test for a linear trend. The strongest inverse associations appeared in Black men and White women. Black men in the high Ca(2+) intake group were leaner than those in the low Ca(2+) intake group: BMI 23.4 +/- 0.9 vs. 26.7 +/- 1.1 kg/m(2) (P = 0.01); for all other adiposity measures, P < 0.05. In White women, regression analyses showed significant inverse associations between Ca(2+) intake and BMI (P = 0.02), %FAT (P = 0.001), TAF (P = 0.006), AVF (P = 0.03), and ASF (P = 0.01). The percentage of fat of White men in the highest Ca(2+) intake group was significantly lower than in the lowest Ca(2+) group (P = 0.04). No significant associations were found in Black women. Low Ca(2+) intake may be associated with higher adiposity, particularly in men and White women.

We recently reported that a genomic region close to the leptin locus was linked to fasting insulin response to exercise training in nondiabetic white subjects. We tested the hypothesis that common exonic variants in the leptin (LEP) and leptin receptor (LEPR) genes modify the effects of regular physical activity on glucose homeostasis in nondiabetic whites (n = 397) and blacks (n = 143). In whites, exercise increased insulin sensitivity index (P = 0.041) and disposition index (P = 0.046) in the LEPR 109R allele carriers but not in the K109K homozygotes, increased glucose disappearance index more in the R109R homozygotes than in the K109 allele carriers (P = 0.039), and decreased fasting glucose only in the 109R allele carriers (P = 0.018). We also found an interaction between the LEP A19G and LEPR K109R polymorphisms on the change in fasting insulin in whites (P = 0.010). The association between the LEP A19G polymorphism and the change in insulin was evident only in the LEPR 109R carriers (P = 0.019). The decrease in insulin was strongest in the LEP A19A homozygotes who carried the LEPR 109R allele. Similar interaction was observed in blacks (P = 0.046). Variations in the LEP and LEPR genes are associated with the magnitude of the effects of regular exercise on glucose homeostasis in nondiabetic individuals.

Background: A poor diet is a risk factor for chronic diseases such as obesity, cardiovascular disease, hypertension, and some cancers. Twin and family studies suggest that genetic factors potentially influence energy and nutrient intakes. Objective: We sought to identify genomic regions harboring genes affecting total energy, carbohydrate, protein, and fat intakes. Design: We performed a genomic scan in 347 white sibling pairs and 99 black sibling pairs. Dietary energy and nutrient intakes were assessed by using Willett's food-frequency questionnaire. Single-point and multipoint Haseman-Elston regression techniques were used to test for linkage. These subjects were part of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a multicenter project undertaken by 5 laboratories. Results: In the whites, the strongest evidence of linkage appeared for dietary energy and nutrient intakes on chromosomes 1p21.2 (P = 0.0002) and 20q 13.13 (P = 0.00007), and that for fatintake appeared on chromosome 12q14.1 (P = 0.0013). The linkage evidence on chromosomes 1 and 20 related to total energy intake rather than to the intake of specific macronutrients. In the blacks, promising linkages for macronutrient intakes occurred on chromosomes 12q23-q24.21, 1q32.1, and 7q 11.1. Several potential candidate genes are encoded in and around the linkage regions on chromosomes 1p21.2, 12q14.1, and 20q13.13. Conclusions: These are the first reported human quantitative trait loci for dietary energy and macronutrient intakes. Further study may refine these quantitative trait loci to identify potential candidate genes for energy and specific macronutrient intakes that would be amenable to more detailed molecular studies.

The purpose of this study was to identify regions of the human genome linked to maximal oxygen uptake (V̇o2 max) and maximal power output (MPO), and their response to a standardized 20-wk endurance-training program in sedentary black and white subjects. A total of 509 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan. Baseline phenotypes were adjusted for age, sex, and body mass, whereas the training responses were adjusted for age, sex, and the baseline values. Regression-based single- and multipoint linkage analyses were used. In the sedentary state, a total of 351 and 102 sibling pairs were available for whites and blacks, respectively, and 329 and 90 sibling pairs, respectively, for the training response phenotypes. Baseline V̇o2 maxshowed promising linkage ( P < 0.0023) with 11p15.1 (whites), and suggestive evidence of linkage (0.01 > P > 0.0023) was found on 1p31, 7q32, and 7q36 (blacks). Baseline MPO exhibited promising linkage on 10q23 and suggestive evidence of linkage on 13q33 and 18q11-q12 (whites). V̇o2 maxtraining response yielded promising linkages with markers on 1p31 (blacks) and suggestive on 4q27, 7q34, and 13q12 (whites) and on 16q22 and 20q13.1 (blacks). Training-induced changes in MPO showed promising linkages on 5q23 (whites) and suggestive on 1q21, 4p15.1, and 4p13 (whites) and on 1q22 and 13q11 (blacks). In conclusion, the strongest evidence of linkage was found on chromosomal regions 11p15 and 10q23 for V̇o2 maxand MPO in the sedentary state and on chromosomes 1p31 and 5q23 for their responsiveness to training. These chromosomal regions harbor several candidate genes that deserve further investigation.