Abstract P236: The Heritability of Submaximal Exercise Heart Rate Response to Regular Exercise is Accounted for by Nine SNPs

Regular physical activity is the most effective non-pharmacological strategy to lower heart rate both at rest and during submaximal physical work. We have previously shown that endurance training-induced changes in heart rate are heritable (h 2 =0.34). However, few genes associated with heart rate training responses have been identified. The purpose of this study was to perform a genome-wide association study (GWAS) to uncover DNA sequence variants associated with submaximal exercise heart rate training responses in the HERITAGE Family Study. Heart rate was measured during steady-state exercise at 50 Watts (HR50) on two separate days both before and after a 20-week endurance training program in 473 white subjects from 99 families. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using Illumina BeadStation 500GX platform. After quality control procedures, 320,000 single-nucleotide polymorphisms (SNPs) were available for the GWAS analyses. Associations between HR50 training response (ΔHR50) and the SNPs were tested using the MERLIN software package (single-SNP analyses) and standard regression models (multivariate analyses). Furthermore, conditional heritability analysis (MERLIN) was used to test the contribution of the most significant SNPs to the heritability of ΔHR50. Exercise training induced an average reduction of 11 bpm in HR50 (SD = 9.9 bpm, p<0.0001), while individual training responses ranged from a 12 bpm increase to a 42 bpm decrease. The strongest associations for ΔHR50 (adjusted for age, sex, BMI and baseline HR50) were detected with SNPs at the YWHAQ locus on chromosome 2p25 (p=8.1x10 -7 ), RBPMS locus on 8p12 (p=3.8x10 -6 ) and CREB1 locus on 2q34 (p=1.6x10 -5 ). In addition, 37 other SNPs showed p-values < 9.9x10 -5 . After removing redundant SNPs, the ten most significant SNPs explained 35.9% of the ΔHR50 variance in a multivariate regression model. Conditional heritability test showed that nine of these SNPs (all intragenic) accounted for 100% of the ΔHR50 heritability. Our results indicate that SNPs in nine genes related to cardiomyocyte and neuronal functions as well as cardiac memory formation fully account for the heritability of submaximal exercise heart rate response to regular physical activity in the HERITAGE Family Study.