SNPs from 17 Genes and Symptom-limited Exercise Test Duration Over 20 years: The Cardia Fitness Study

Background: Over 200 genes have been associated with health-related fitness phenotypes, including markers in genes related to energy metabolism, hypoxia, and cardiac, endothelial, skeletal, sympathetic, and vascular function. PURPOSE: To examine the associations of gene variants with exercise duration during a symptom-limited treadmill test at baseline (B_duration) and with changes in exercise duration over 20 years (Δ20_duration). METHODS: We examined 3779 and 2337 participants with data for B_duration and Δ20_duration, respectively, from the CARDIA study. Treadmill time was determined based on the duration of a symptom-limited graded exercise test (modified Balke protocol). Mean B_duration was 8.9±2.8 and 10.7±2.6 min and mean Δ20_duration was -3.0±2.1 and -2.8±2.0 min in blacks and whites, respectively. 217 SNPs in blacks and 171 SNPs in whites from 17 genes were examined. RESULTS: In blacks, 5 SNPs in the ATP1A2, HIF1A, NOS3, and PPARGC1A loci were associated with B_duration in a multivariate regression model (p-value range 0.0036-0.0374). Analyses involving a multimarker construct found that blacks (n=99) with the most favorable genotypes at these 5 SNPs had the longest B_duration (P<0.0001). Similar analyses in whites found that the HIF1A rs1957757 and PPARGC1A rs3774909 markers were associated with B_duration (P=0.0065 and 0.0244, respectively), and a multimarker construct found that whites (n=17) with the most favorable genotypes at both SNPs had a 3 min longer B_duration compared to those with none of the favorable genotypes (P=0.0041). No SNPs were significantly associated with Δ20_duration in the multivariate regression analyses in blacks. Conversely, in whites, 4 SNPs in the AGT, AMPD1, ANG, and PPARGC1A loci were associated with Δ20_duration in a multivariate regression model (p-value range 0.0018-0.0183). Analyses involving a multimarker construct found that whites (n=48) with the most favorable genotypes at these 4 SNPs had less decline in treadmill duration over 20 years (P<0.0001). CONCLUSION: We conclude that alleles at genes related to skeletal muscle Na+/K+ transport, hypoxia, and mitochondrial metabolism are weakly associated with symptom-limited exercise test duration and change in duration over time in adults.