Treva Rice

Familial resemblance for VO2max in the sedentary state: the HERITAGE family study

This study investigates the familial resemblance of maximal oxygen uptake (VO2max) based on data from 86 nuclear families of Caucasian descent participating in the HERITAGE Family Study. In the current study, VO2max was measured twice on a cycle ergometer in 429 sedentary individuals (170 parents and 259 of their offspring), aged between 16 and 65 yr. The VO2max was adjusted by regression procedures for the effects of 1) age and sex; 2) age, sex, and body mass; and 3) age, sex, body mass, fat mass, and fat-free mass, as determined by underwater weighing. Evidence for significant familial resemblance was observed for each of the three VO2max phenotypes. Spouse, sibling, and parent-offspring correlations were significant, suggesting that both genetic and environmental factors contribute to the familial resemblance for VO2max. Maximal heritability estimates were at least 50%, a value inflated to an undetermined degree by nongenetic factors. The hypothesis of maternal inheritance, with the fathers contribution being environmental, was also found to fit the data with estimates of maternal heritability, potentially associated in part with mitochondrial inheritance, reaching about 30%. These results suggest that genetic and nongenetic factors as well as maternal influences contribute to the familial aggregation of VO2max in sedentary individuals.

Genome-Wide Linkage Analysis of Systolic and Diastolic Blood Pressure The Québec Family Study

BackgroundBlood pressure (BP), an important risk factor for coronary heart disease, is a complex trait with multiple genetic etiologies. While some loci affecting BP variation are known (eg, angiotensinogen), there are likely to be novel signals that can be detected with a genome scan approach. Methods and ResultsA genome-wide scan was performed in 125 random and 81 obese families participating in the Québec Family Study. A multipoint variance-components linkage analysis of 420 markers (353 microsatellites and 67 restriction fragment length polymorphisms) revealed several signals (P <0.0023) for systolic BP on 1p (D1S551, ATP1A1), 2p (D2S1790, D2S2972), 5p (D5S1986), 7q (D7S530), 8q (CRH), and 19p (D19S247). Suggestive evidence (0.0023<P <0.01) was found on 3q, 10p, 12p, 14q, and 22q. The results were encouraging for HSD3B1 (P <0.03), AGT (P <0.03), ACE (P <0.02), and adipsin (P <0.005) but null with regard to other candidates (eg, renin, and glucocorticoid and adrenergic receptors). ConclusionsMultiple linkage regions support the notion that risk for hypertension is due to multiple (ie, oligogenic) susceptibility loci. Comparisons across the complete, random, and obese samples suggest that some regions are specific to BP and others may involve obesity (eg, pleiotropy, epistasis, or gene-environment interaction). Some of these areas harbor known candidates. Others involve novel regions, some of which replicate previous reports and provide a focus for future studies to identify novel genes that influence interindividual variation in BP.

Genomic predictors of the maximal O2 uptake response to standardized exercise training programs

Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O(2) uptake (VO(2max)) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genome-wide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in VO(2max) Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 × 10(-4). Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in VO(2max) trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their VO(2max) by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ~6% of the training response of VO(2max). The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDM1); glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A); K(+) channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ~68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in VO(2max) in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of Vo(2max) to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted.

Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study.

BACKGROUND Since insulin resistance is thought to be the underlying mechanism for metabolic syndrome, affected individuals might be sensitive to a dietary sodium intervention. We aimed to examine the association between metabolic syndrome and salt sensitivity of blood pressure. METHODS 1906 Chinese participants without diabetes, aged 16 years or more, were selected to receive a low-sodium diet (51.3 mmol per day) for 7 days followed by a high-sodium diet (307.8 mmol per day) for an additional 7 days. Participants were excluded from the analysis if metabolic risk factor information was missing or if they did not complete their dietary interventions. Blood pressure was measured at baseline and on days 2, 5, 6, and 7 of each intervention. Metabolic syndrome was defined as the presence of three or more of: abdominal obesity, raised blood pressure, high triglyceride concentration, low HDL cholesterol, or high glucose. High salt sensitivity was defined as a decrease in mean arterial blood pressure of more than 5 mm Hg during low-sodium or an increase of more than 5 mm Hg during high-sodium intervention. This study is registered with ClinicalTrials.gov, number NCT00721721. FINDINGS Of the 1881 participants with information regarding metabolic syndrome, 283 had metabolic syndrome. 1853 participants completed the low-sodium diet and 1845 completed the high-sodium diet. Multivariable-adjusted mean changes in blood pressure were significantly greater in participants with metabolic syndrome than in those without on both low-sodium and high-sodium diets (p<0.0001 for all comparisons). Additionally, risk of salt sensitivity rose with increasing numbers of risk factors for metabolic syndrome. Compared with those with no risk factors, participants with four or five had a 3.54-fold increased odds (95% CI 2.05-6.11) of high salt-sensitivity during the low-sodium and a 3.13-fold increased odds (1.80-5.43) of high salt-sensitivity during the high-sodium intervention. INTERPRETATION These results suggest that metabolic syndrome enhances blood pressure response to sodium intake. Reduction in sodium intake could be an especially important component in reducing blood pressure in patients with multiple risk factors for metabolic syndrome.

Blood lipid response to 20 weeks of supervised exercise in a large biracial population: The HERITAGE family study

We studied the effects of 20 weeks of supervised cycle-ergometer exercise on plasma lipids in 675 healthy, sedentary, normolipidemic white and black men and women aged 17 to 65 years, participating in the HERITAGE Family Study. Fasting plasma lipids were assessed twice at baseline and 24 and 72 hours after the last exercise session and adjusted for plasma volume changes. No significant differences from the mean baseline levels were observed for total, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B (Apo B). A significant reduction (P < .01) from baseline levels in plasma total and VLDL triglycerides was observed only in the 24-hour posttraining specimens, reflecting a response to the last bout of exercise. High-density lipoprotein (HDL) cholesterol increased 3.6% for the combined group, primarily due to an increase in HDL2, with an associated increase in Apo A-1 (P < .001). No significant differences were noted in the HDL response by sex, race, or age. An inverse correlation (r = -.241) was observed between the increase in HDL cholesterol and change in body fat only in men, and the increase in HDL cholesterol was unrelated to the change in maximal oxygen uptake (VO2max).

Methods for handling multiple testing.

The availability of high-throughput genotyping technologies and massive amounts of marker data for testing genetic associations is a dual-edged sword. On one side is the possibility that the causative gene (or a closely linked one) will be found from among those tested for association, but on the other testing, many loci for association creates potential false positive results and the need to accommodate the multiple testing problem. Traditional solutions involve correcting each test using adjustments such as a Bonferroni correction. This worked well in settings involving a few tests (e.g., 10-20, as is typical for candidate gene studies) and even when the number of tests was somewhat larger (e.g., a few hundred as in genome-wide microsatellite scans). However, the current dense single nucleotide polymorphism (SNP) and/or whole-genome association (WGA) studies often consider several thousand to upwards of 500,000 and 1 million SNPs. In these settings, a Bonferroni correction is not practical as it does not take into account correlations between the tests due to linkage disequilibrium and hence can be too conservative. The effect sizes of susceptibility alleles will rarely (if ever) reach the required level of significance in WGA studies if a Bonferroni correction is used, and the number of false negatives is likely to be large. Thus, one of the burning methodological issues in contemporary genetic epidemiology and statistical genetics is how to balance false positives and false negatives in large-scale association studies. This chapter reviews developments in this area from both historical and current perspectives.

Familial aggregation of physical activity levels in the Québec family study

PURPOSE Familial aggregation of physical activity phenotypes was investigated in 696 subjects from 200 families of the Quebec Family Study. The mean age of offspring and parents was 27 and 53 yr, respectively. METHODS The levels of physical activity were estimated using a 3-d diary and a questionnaire dealing with physical activity during the past year. RESULTS An ANOVA performed on the age and sex adjusted physical activity phenotypes revealed that there were 1.40-1.52 times more variation in physical activity levels between families than within families (0.001 < P < 0.0001), suggesting that physical activity levels aggregate in families. Maximal heritabilities (SEGPATH), adjusted for the degree of spouse resemblance, reached 25%, 16%, 19%, and 17% for the degree of inactivity, time spent in moderate to strenuous physical activities, total level of daily activity, and weekly time spent in the main activity during the previous year, respectively. CONCLUSION These results suggest that physical activity level is characterized by a significant degree of familial resemblance, and that inactivity has a slightly higher heritability level than moderate to strenuous physical activity or total physical activity phenotypes. The pattern of familial correlations suggests that shared familial environmental factors along with genetic factors are also important in accounting for the familial resemblance in physical activity level.

Familial resemblance for abdominal visceral fat : the HERITAGE family study

OBJECTIVES: Abdominal visceral fat (AVF) is considered a risk factor for diabetes, atherogenic lipid profiles and hypertension. However, little is known about the genetic contribution to AVF as compared to total body fat. DESIGN: AVF was assessed by computerized tomography, and total body fat (fat mass) was assessed by underwater weighing in 86 families participating in the Heritage Family Study. All family members were sedentary at baseline examination. The familial factors underlying the variability in age-adjusted AVF, age-fat mass-adjusted AVF and age-adjusted fat mass, were assessed using a familial correlation model. RESULTS: The maximal heritability (including genetic and familial environmental effects) for AVF was comparable before (47%) and after (48%) adjusting for fat mass, and was 55% for fat mass itself in these sedentary families. Spouse correlations were significant for fat mass and for AVF prior to, but not after, adjustment for fat mass. CONCLUSIONS: These results confirm the only previous study which investigated the familial aggregation of AVF (both in pattern and magnitude), suggesting that the factors underlying AVF in these sedentary families may be similar to those in the population at large. Although both genetic and familial environmental factors probably influence each of fat mass and AVF, there appears to be a predominantly genetic etiology for the visceral component which is independent of total body fat. These findings imply that some individuals are more at risk than others because of an inherited tendency to store abdominal fat viscerally rather than subcutaneously.

Familial Resemblance of Plasma Lipids, Lipoproteins and Postheparin Lipoprotein and Hepatic Lipases in the HERITAGE Family Study

The familial aggregation of lipids and lipoproteins and plasma postheparin triglyceride lipases was investigated in 86 Caucasian families participating in the HERITAGE Family study, a study investigating the role of genetic factors in the adaptation to exercise training and its relationships with cardiovascular disease risk factors. Accordingly, sedentary subjects were recruited, tested for a battery of measurements, exercise trained for 20 weeks, and were re-measured. The present report includes plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, and postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities measured in 437 sedentary individuals (171 parents and 266 adult offspring) before training. Significant familial resemblance was observed for all the age-adjusted phenotypes. The pattern of familial correlations reveals no spouse correlations but significant parent-offspring and sibling correlations for total cholesterol, HDL-cholesterol and LDL-cholesterol with heritability (h2) estimates of 62%, 83%, and 50%, respectively. For plasma triglyceride concentrations (h2 = 55%) and HL activity (h2 = 40%), significant spouse correlations were found in addition to parent-offspring and sibling correlations, suggesting that common familial environment in addition to genetic factors contribute to the familial resemblance. For plasma LPL activity, there was no spouse correlation, but sex differences were found in the familial correlations with higher heritabilities in female pairs (h2 = 76%) compared to male pairs (h2 = 30%) and opposite-sex pairs (h2 = 44%). These results confirm the findings of previous family studies showing that genetic factors are major determinants of the familial resemblance in plasma lipids and lipoproteins and suggest the presence of sex differences in the heritability of postheparin LPL activity.

Heart rate and blood pressure changes with endurance training: the HERITAGE Family Study.

PURPOSE The purpose of this study was to determine the magnitude of change in resting and exercise heart rate (HR) and blood pressure (BP), by race, sex, and age, after a 20-wk endurance training program in 507 healthy and previously sedentary subjects from the HERITAGE Family Study. METHODS After baseline measurements, subjects exercised on cycle ergometers 3 d x wk(-1) for a total of 60 exercise sessions starting at 55% of VO2max for 30 min x session(-1) and building to 75% of VO2max for 50 min x session(-1) for the last 6 wk. HR and BP at rest and during exercise (50 W, 60% of VO2max maximal exercise) were each determined in duplicate on two different days both before and after training (resting values at 24-h and 72-h posttraining). RESULTS After the period of training, there was a small decrease in resting HR (-2.7 to -4.6 beats x min(-1) across groups at 72-h posttraining), and small changes (i.e., < 3 mm Hg) in resting systolic (SBP), diastolic (DBP), and calculated mean BP (MBP), which varied by race, sex, and age. During exercise at the same absolute work rate (50 W), HR, SBP, DBP, and MBP were all significantly reduced, with greater reductions in HR in women compared with men, and greater reductions in BP in blacks and older subjects compared with whites and younger subjects, respectively. At the same relative work rate (60% VO2max), HR, DBP, and MBP were reduced, but SBP remained unchanged. Blacks had a greater reduction in DBP, but whites had a greater reduction in HR. Finally, at maximal exercise, there was a small decrease in HR, with men and whites decreasing more than women and blacks; an 8 mm Hg increase in SBP, with men increasing more than women; a 4 mm Hg decrease in DBP, with blacks decreasing more than whites; and no change in MBP. CONCLUSION In conclusion, the reductions in resting HR and BP with training were generally small, but the reductions during exercise were substantial and clinically important, with the older and the black populations experiencing greater reductions.