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

Abstract

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.

Figures

Fig. 1.

Distribution of the maximal O2 uptake (V̇o2max) training responses in whites in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study.

Fig. 2.

A Manhattan summary plot of the V̇o2max training response genome-wide association study (GWAS) results across 22 autosomes. Chromosomes are on the x-axis, and P values are shown on the y-axis as −log10 of P.

Fig. 3.

Age, sex, and baseline V̇o2max-adjusted V̇o2max training responses across nine GWAS predictor single-nucleotide polymorphism (SNP) score categories in HERITAGE whites. Numbers of subjects within each SNP score category are indicated inside each histogram bar. Le, “less or equal to;” ge, “greater or equal to.”

Fig. 4.

Association of SNP rs11715829 with age, sex, and baseline V̇o2max-adjusted V̇o2max training responses in Studies of a Targeted Risk Reduction Intervention in Defined Exercise (STRRIDE) whites (left) and HERITAGE whites (right). P values for the main effect of genotype in each cohort are shown at the top of each graph. Numbers of subjects with each genotype are indicated inside each histogram bar (no STRRIDE whites had the G/G genotype).

Fig. 5.

Association of calmodulin-binding transcription activator 1 (CAMTA1) SNP rs884736 (top) and regulator of G protein signaling 18 (RGS18) SNPs rs17581162 and rs10921078 (bottom) with age, sex, and baseline V̇o2max-adjusted V̇o2max training responses in HERITAGE blacks (left) and whites (right). P values for the main effect of genotype in each cohort are shown at the top of each graph. Numbers of subjects with each genotype are indicated inside each histogram bar. GWAS SNP rs10921078 in HERITAGE whites was replaced with rs17581162 in the replication experiments (see methods).

Fig. 6.

Association of SNP rs1956197 with age, sex, and baseline V̇o2max-adjusted V̇o2max training responses in Dose Response to Exercise (DREW) whites (left) and HERITAGE whites (right). P values for the main effect of genotype in each cohort are shown at the top of each graph. Numbers of subjects with each genotype are indicated inside each histogram bar.

Fig. 7.

Association of SNPs rs17117533 and rs824205 [75 kb upstream of necdin (NDN)] with age, sex, and baseline V̇o2max-adjusted V̇o2max training responses in DREW whites (left) and HERITAGE whites (right). P values for the main effect of genotype in each cohort are shown at the top of each graph. Numbers of subjects with each genotype are indicated inside each histogram bar. GWAS SNP rs824205 in HERITAGE whites was replaced with rs17117533 in the replication experiments (see methods).