Regular exercise and patterns of response across multiple cardiometabolic traits: the HERITAGE family study.

OBJECTIVES: We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits. METHODS: A 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. RESULTS: Only 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. CONCLUSIONS: Interindividual 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.

Precision exercise medicine: understanding exercise response variability.

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels-a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability.

Plasma steroids, body composition, and fat distribution: effects of age, sex, and exercise training.

BACKGROUND/OBJECTIVES: 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. SUBJECTS/METHODS: 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 < 0.0001. RESULTS: Baseline levels of dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone-binding globulin (SHBG), and testosterone (TESTO) were negatively associated with fat mass and abdominal fat (P < 0.0001) in men and for SHBG in women (P < 0.0001). TESTO was not correlated with fat-free mass in men or women, but was significantly associated with % fat-free mass in men. No association was detected between baseline steroid hormone levels and changes in adiposity traits in response to 20 weeks of exercise. CONCLUSION: In men, low DHT, OHPROG, SHBG, and TESTO were associated with higher adiposity and abdominal and visceral fat. A similar adiposity profile was observed in women with low SHBG.

Effects of bioDensity Training and Power Plate Whole-Body Vibration on Strength, Balance, and Functional Independence in Older Adults.

Reduced strength, balance, and functional independence diminish quality of life and increase health care costs. Sixty adults (82.2 ± 4.9 years) were randomized to a control or three 12-week intervention groups: bioDensity (bD); Power Plate (PP) whole-body vibration (WBV); or bD+PP. bD involved one weekly 5-s maximal contraction of four muscle groups. PP involved two 5-min WBV sessions. Primary outcomes were strength, balance, and Functional Independence Measure (FIM). No groups differed initially. Strength significantly increased 22-51% for three muscle groups in bD and bD+PP (P < .001), with no changes in control and PP. Balance significantly improved in PP and bD+PP but not in control or bD. bD, PP, and bD+PP differentially improved FIM self-care and mobility. Strength improvements from weekly 5-min sessions of bD may impart health/clinical benefits. Balance and leg strength improvements suggest WBV beneficially impacts fall risk and incidence. Improved FIM scores are encouraging and justify larger controlled trials on bD and bD+PP efficacy.

Ventilatory Threshold Related to V̇O 2 reserve, Heart Rate Reserve, and Rating of Perceived Exertion in a Large Varied Sample.

PURPOSE: ACSM guidelines state that aerobic exercise intensity should be 30%/40% to 89% V̇O 2 reserve (V̇O 2 R) or heart rate reserve (HRR). Determining the proper intensity within this range is the "art" of exercise prescription, often relying on rating of perceived exertion (RPE) as the adjunctive intensity modulator. Current guidelines do not consider the use of ventilatory threshold (VT) due to the need for specialized equipment and methodological issues. The purpose of this investigation was to evaluate VT related to V̇O 2peak , V̇O 2 R, HRR, and RPE across the full spectrum of very low to very high V̇O 2peak values. METHODS: Eight hundred and sixty-three records of exercise tests were retrospectively examined. Data were stratified for V̇O 2peak , activity level, age, test modality, and sex. RESULTS: When stratified for V̇O 2peak , V̇O 2 at VT (V̇O 2 vt) had a lower mean value of ~14 mL·kg -1 ·min -1 in the lowest fit, rose gradually until median V̇O 2peak , and rose steeply thereafter. When graphed relative to V̇O 2peak , V̇O 2 vt as a percentage of V̇O 2 R (VT%V̇O 2 R) resembled a U-shaped curve, with a nadir ~43% V̇O 2 R at V̇O 2peak ~40 mL·kg -1 ·min -1 . Average VT%V̇O 2 R increased to ~75% in groups with the lowest or highest V̇O 2peak . There was a large variance in the value of VT at all V̇O 2peak levels. Mean RPE at VT was 12.5 ± 0.93, regardless of V̇O 2peak . CONCLUSIONS: Given the relationship of VT as the transition from moderate- to higher-intensity exercise, these data may help the understanding of aerobic exercise prescription in persons across the spectrum of V̇O 2peak values.

Effect of individual characteristics and aerobic training on the %HRR-%V̇O2R 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.

Effect of steady-state aerobic exercise intensity and duration on the relationship between reserves of heart rate and oxygen uptake.

Background: The percentages of heart rate (%HRR) or oxygen uptake (%V̇O2R) reserve are used interchangeably for prescribing aerobic exercise intensity due to their assumed 1:1 relationship, although its validity is debated. This study aimed to assess if %HRR and %V̇O2R show a 1:1 relationship during steady-state exercise (SSE) and if exercise intensity and duration affect their relationship. Methods: Eight physically active males (age 22.6 ± 1.2 years) were enrolled. Pre-exercise and maximal HR and V̇O2 were assessed on the first day. In the following 4 days, different SSEs were performed (running) combining the following randomly assigned durations and intensities: 15 min, 45 min, 60% HRR, 80% HRR. Post-exercise maximal HR and V̇O2 were assessed after each SSE. Using pre-exercise and post-exercise maximal values, the average HR and V̇O2 of the last 5 min of each SSE were converted into percentages of the reserves (%RES), which were computed in a 3-way RM-ANOVA (α = 0.05) to assess if they were affected by the prescription parameter (HRR or V̇O2R), exercise intensity (60% or 80% HRR), and duration (15 or 45 min). Results: The %RES values were not affected by the prescription parameter (p = 0.056) or its interactions with intensity (p = 0.319) or duration and intensity (p = 0.117), while parameter and duration interaction was significant (p = 0.009). %HRRs and %V̇O2Rs did not differ in the 15-min SSEs (mean difference [MD] = 0.7 percentage points, p = 0.717), whereas %HRR was higher than %V̇O2R in the 45-min SSEs (MD = 6.7 percentage points, p = 0.009). Conclusion: SSE duration affects the %HRR-%V̇O2R relationship, with %HRRs higher than %V̇O2Rs in SSEs of longer duration.

The HERITAGE Family Study: A Review of the Effects of Exercise Training on Cardiometabolic Health, with Insights into Molecular Transducers.

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.

HRR and V˙O2R Fractions Are Not Equivalent: Is It Time to Rethink Aerobic Exercise Prescription Methods?

INTRODUCTION: According to current guidelines, the intensity of health-enhancing aerobic exercise should be prescribed using a percentage of heart rate reserve (%HRR), which is considered to be more closely associated (showing a 1:1 relation) with the percentage of oxygen uptake reserve (%V˙O2R) rather than with the percentage of maximal oxygen uptake (%V˙O2max) during incremental exercise. However, the associations between %HRR and %V˙O2R and between %HRR and %V˙O2max are under debate; hence, their actual relationships were investigated in this study. METHODS: Data from each stage of a maximal incremental exercise test performed by 737 healthy and physically inactive participants of the HERITAGE Family Study were screened and filtered then used to calculate the individual linear regressions between %HRR and either %V˙O2R or %V˙O2max. For each relationship, the mean slope and intercept of the individual linear regression were compared with 1 and 0 (i.e., the identity line), respectively, using one-sample t-tests. The individual root mean square errors of the actual versus the 1:1 predicted %HRR were calculated for both relationships and compared using a paired-sample t-test. RESULTS: The mean slopes (%HRR-%V˙O2R, 0.972 ± 0.189; %HRR-%V˙O2max, 1.096 ± 0.216) and intercepts (%HRR-%V˙O2R, 8.855 ± 16.022; %HRR-%V˙O2max, -3.616 ± 18.993) of both relationships were significantly different from 1 and 0, respectively, with high interindividual variability. The average root mean square errors were high and revealed that the %HRR-%V˙O2max relationship was more similar to the identity line (P < 0.001) than the %HRR-%V˙O2R relationship (7.78% ± 4.49% vs 9.25% ± 5.54%). CONCLUSIONS: Because both relationships are different from the identity line and using a single equation may not be appropriate to predict exercise intensity at the individual level, a rethinking of the relationships between the intensity variables may be necessary to ensure that the most suitable health-enhancing aerobic exercise intensity is prescribed.

Adropin: An endocrine link between the biological clock and cholesterol homeostasis.

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-ß-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.

Effects of regular endurance exercise on GlycA: Combined analysis of 14 exercise interventions.

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 ±â€¯1.8 µmol/L). This reduction remained significant (-9.12 ±â€¯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 < 0.0001). 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.

CETP genotypes and HDL-cholesterol phenotypes in the HERITAGE Family Study.

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, HDL(2)-c, HDL(3)-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 HDL(3)-c (P = 0.004) and apoA1 (P = 0.02) training responses in whites. In women, the -629 A/A homozygotes showed greater increases in HDL(3)-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 HDL(3)-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.

Effect of exercise training on in vitro LDL oxidation and free radical-induced hemolysis: the HERITAGE Family Study.

Oxidant stress and overproduction of reactive oxygen species (ROS) contribute to the development of cardiovascular disease. Oxidative modifications of low-density lipoproteins (LDL) are thought to play an early and critical role in atherogenesis. LDL oxidation can be reproduced in vitro, but results usually show a large interindividual variation not entirely explained by the environment. Free radical-induced hemolysis is also proposed to reveal the overall antioxidant capacity. The roles of genetic factors and exercise on the variability of both measures were investigated. The study was conducted in 146 healthy individuals from 28 families participating in a 20-week exercise-training program. In addition to important biological and environmental influences on variation, significant familial aggregation was detected in all oxidation measures. Exercise did not significantly modify the LDL oxidation parameters, but significantly increased resistance was observed in the free radical-induced hemolysis, especially in women, this effect was not observed in smokers. In total, the findings suggest the presence of familial effects in the response to ex vivo oxidation. Further, smoking negates the beneficial effect of exercise training on erythrocyte resistance to free radical-induced hemolysis. These observations emphasize the importance of context in the evaluation of exercise and oxidant stress.

Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial.

CONTEXT: Low levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity-fitness dose response relation remains. OBJECTIVE: To examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area. INTERVENTION: Participants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak Vo2. MAIN OUTCOME MEASURE: The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption (Vo2abs, L/min). RESULTS: The mean (SD) baseline Vo2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their Vo2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P<.001 for each vs control; P for trend <.001). There was no treatment x subgroup interaction for age, body mass index, weight, baseline Vo2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group. CONCLUSION: In this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00011193.

Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study.

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.

Hepatic lipase gene variant -514C>T is associated with lipoprotein and insulin sensitivity response to regular exercise: the HERITAGE Family Study.

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 microU.min(-1).ml(-1)) than in the TT genotype (+0.27 +/- 0.3 and -0.97 +/- 0.3 microU.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.

Pleiotropic QTL on chromosome 19q13 for triglycerides and adiposity: the HERITAGE Family Study.

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.

The TNF-alpha G-308A polymorphism is associated with C-reactive protein levels: the HERITAGE Family Study.

OBJECTIVE: Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), stimulate the release of C-reactive protein (CRP). We investigated the association between the TNF-alpha 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-alpha 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<0.001 and 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 (> or = 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-alpha G-308A polymorphism is associated with higher plasma CRP levels and less favorable CRP response to regular exercise.

Effects of exercise training on glucose homeostasis: the HERITAGE Family Study.

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 (i.v.GTT). RESEARCH DESIGN AND METHODS: An i.v.GTT 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 i.v.GTT was reduced by 7% (P = 0.02). CONCLUSIONS: Although the effects of structured regular exercise were highly variable, there were improvements in virtually all i.v.GTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis.

Familial aggregation of blood lipid response to exercise training in the health, risk factors, exercise training, and genetics (HERITAGE) Family Study.

BACKGROUND: Fasting levels of plasma lipids and lipoproteins are reported to improve with regular exercise training. However, little is known on whether the training responses are influenced by heritable factors. METHODS AND RESULTS: The lipid profile was assessed in 115 black (224 individuals) and 99 white families (469 individuals), who participated in the HERITAGE Family Study, while in a sedentary state (baseline visit) and after exercise training for 20 weeks (post visit). Variables included total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, and HDL-C subfractions 2 (HDL2-C) and 3 (HDL3-C). Familial correlations for the training responses (Delta=post-baseline) were significant for most variables, and the percent variance accounted for by familial factors (ie, maximal heritabilities) ranged from 25% to 38%. Exceptions were for higher heritabilities near 60% for DeltaApoB in blacks and DeltaHDL2-C in whites and a lower estimate of zero for DeltaLDL-C in blacks. CONCLUSIONS: Heritable factors in part determine lipid profile responses to regular exercise. Maximal heritabilities were similar across ethnic groups and variables, except for DeltaLDL-C, DeltaApoB, and DeltaHDL2-C. Molecular studies to identify the markers and genes associated with these influences are currently underway.