Genome-wide linkage scan for submaximal exercise heart rate in the HERITAGE family study

Abstract

The purpose of this study was to identify regions of the human genome linked to submaximal exercise heart rates in the sedentary state and in response to a standardized 20-wk endurance training program in blacks and whites of the HERITAGE Family Study. A total of 701 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan, with 328 sibling pairs from 99 white nuclear families and 102 pairs from 115 black family units. Steady-state heart rates were measured at the relative intensity of 60% maximal oxygen uptake (HR60) and at the absolute intensity of 50 W (HR50). Baseline phenotypes were adjusted for age, sex, and baseline body mass index (BMI) and training responses (posttraining minus baseline, ⌬) were adjusted for age, sex, baseline BMI, and baseline value of the phenotype. Two analytic strategies were used, a multipoint variance components and a regression-based multipoint linkage analysis. In whites, promising linkages (LOD Ͼ 1.75) were identified on 18q21-q22 for baseline HR50 (LOD ϭ 2.64; P ϭ 0.0002) and ⌬HR60 (LOD ϭ 2.10; P ϭ 0.0009) and on chromosome 2q33.3 for ⌬HR50 (LOD ϭ 2.13; P ϭ 0.0009). In blacks, evidence of promising linkage for baseline HR50 was detected with several markers within the chromosomal region 10q24-q25.3 (peak LOD ϭ 2.43, P ϭ 0.0004 with D10S597). The most promising regions for fine mapping in the HERITAGE Family Study were found on 2q33 for HR50 training response in whites, on 10q25-26 for baseline HR60 in blacks, and on 18q21-22 for both baseline HR50 and ⌬HR60 in whites. exercise training; linkage; quantitative trait loci; genotype IN RECENT YEARS, a large body of evidence has clearly established sedentarism as a risk factor for a number of diseases that become more prevalent with age in both sexes. In contrast, physical activity regularly performed in a variety of settings is considered beneficial because of favorable metabolic and cardiovascular outcomes (9,17,30,31,37,49). Previous studies have shown associations between elevated heart rate (HR) at rest and increased risk of both all-cause and cardiovascular mortality (7,18,21,22,25,26,33). Although HR during submaximal exercise is known to decrease in response to regular endurance training (16, 51), its recovery after maximal and submaximal exercise is considered a powerful predictor of mortality (14, 15). However, interindividual differences in training-induced changes in HR are considerable.In the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study, the steady-state HR at the absolute intensity of 50 W (HR50) and relative intensity of 60% (HR60) of maximal oxygen uptake (V O 2max ) were significantly reduced after 20 wk of endurance training (51). The maximal heritability estimates for baseline HR50 and HR60 reached 59 and 46%, respectively. The maximal heritabilities were 34 and 29% for ⌬HR50 and ⌬HR60, respectively, for the changes in response to a 20-wk endurance training program (⌬, posttraining minus baseline) (5). Furthermore, complex segregation analysis support...

Advances in Exercise, Fitness, and Performance Genomics in 2010

“…CREB1 , found to be so important in this study, would not have been on any list of candidate genes to affect the training-induced change in submaximal exercise HR. Thus, on a larger scale, the use of genome-wide linkage and association studies to identify novel mechanisms involved in the regulation of heritable exercise training response phenotypes has clearly been validated by these HERITAGE studies (2, 43, 44, 55). …”

“…An earlier study from the HERITAGE Family Study assessed genome-wide linkage for submaximal exercise heart rate (HR) responses to exercise training and found the strongest linkage on chromosome 2q34 (55). In 2010, Rankinen and HERITAGE colleagues fine-mapped this region by typing 1450 tagSNPs distributed across 2q34 to identify loci underlying submaximal exercise HR responses to training (43).…”

Genomics and Genetics in the Biology of Adaptation to Exercise

“…QTLs for training-induced changes in submaximal exercise (50 W) SV (ΔSV50) and HR (ΔHR50) were found on chromosomes 10p11 and 2q33.3-q34, respectively (252, 304). The ΔSV50 QTL on 10p11 was narrowed down to a 7 Mb region using dense microsatellite mapping.…”

cAMP Responsive Element Binding Protein 1

“…7 Subsequently, HERITAGE assessed genome-wide linkage of these responses and found the strongest linkage on chromosome 2q34 (logarithm of odds score, 2.10). 8 The present study then typed 1450 tagSNPs distributed over 10 Mb across 2q34 to identify loci underlying these differential HR responses to exercise training and succeeded-perhaps beyond their wildest dreams! In their total SNP association model, two SNPs slightly upstream of the cAMP responsive element binding protein 1 gene showed the strongest association with HR response to training.…”