Heritability of submaximal exercise heart rate response to exercise training is accounted for by nine SNPs

Endurance training-induced changes in hemodynamic traits are heritable. However, few genes associated with heart rate training responses have been identified. The purpose of our study was to perform a genome-wide association study 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 W (HR50) on 2 separate days before and after a 20-wk endurance training program in 483 white subjects from 99 families. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. After quality control procedures, 320,000 single-nucleotide polymorphisms (SNPs) were available for the genome-wide association study analyses, which were performed using the MERLIN software package (single-SNP analyses and conditional heritability tests) and standard regression models (multivariate analyses). The strongest associations for HR50 training response adjusted for age, sex, body mass index, and baseline HR50 were detected with SNPs at the YWHAQ locus on chromosome 2p25 ( P = 8.1 × 10−7), the RBPMS locus on chromosome 8p12 ( P = 3.8 × 10−6), and the CREB1 locus on chromosome 2q34 ( P = 1.6 × 10−5). In addition, 37 other SNPs showed P values <9.9 × 10−5. After removal of redundant SNPs, the 10 most significant SNPs explained 35.9% of the ΔHR50 variance in a multivariate regression model. Conditional heritability tests 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 the submaximal heart rate training response.

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Abstract P261: Genome-wide Association Study of Susceptibility to Particulate Matter-associated Reduced Heart Rate Variability

Circulation ◽

10.1161/circ.133.suppl_1.p261 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Rahul Gondalia ◽

Christy L Avery ◽

Melanie D Napier ◽

Raúl Méndez Giráldez ◽

James D Stewart ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Particulate Matter ◽

Association Study ◽

Repeated Measures ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Total N ◽

Genome Wide ◽

A Genome

Background: Heart rate variability (HRV) is a heritable electrocardiographic measure of cardiac autonnomic control that is consistently and inversely associated with ambient particulate matter (PM) air pollution and risk of both incident cardiovascular disease, and death. However, genetic susceptibility to PM-associated decreases in HRV has not been characterized. Methods: To characterize such susceptibility in a genome-wide context, we conducted cohort-, race/ethnicity-, and sex-stratified longitudinal analyses of ten Women’s Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (total n: 27,121; mean age: 64.6 yr; 81% female; 25% black; 7% Hispanic; mean visits/person: 2.5). In each subpopulation, we log-transformed three previously validated and reliable measures of HRV: RR interval duration (RR); root mean square of successive differences in normal-to-normal RR (RMSSD); and standard deviation of normal-to-normal RR (SDNN). We also estimated mean concentrations of PM < 10 μm on the day of and before HRV measurement. We then used generalized estimating equations (GEE) methods adapted for low prevalence exposure to leverage the repeated measures of HRV and PM10. The GEE models estimated interactions between approximately 2.5 million single nucleotide polymorphisms (SNPs) and PM10 concentrations dichotomized at subpopulation-specific 90th percentiles, while adjusting for age, geographic region or center, season, calendar year, and ancestry. We combined the SNP x PM10 interaction estimates in a Bayesian meta-analysis accounting for ancestral heterogeneity to identify trans-ethnic interactions exceeding genome-wide thresholds: log10 Bayes Factor (BF) > 6 and posterior probability of heterogeneity (PHet) < 0.5. Results: Preliminary analyses of RMSSD provided suggestive evidence of a trans-ethnically important interaction at five SNPs on one locus. The lead SNP (rs17809071; T allele frequency range: 3-16%) is located on chromosome 4, 120 kilobases downstream from SPRY1 (log10BF = 5.31; PHet = 0.14). SPRY1 encodes sprouty receptor tyrosine kinase signaling antagonist 1 which is expressed in cardiac fibroblasts, antagonizes cytokine-induced epicardial fibrosis, and inhibits adipogenesis. Conclusions: Findings from this genome-wide association study of SNP x PM10 interactions suggest that genetic factors may affect susceptibility to PM10-associated decreases in HRV among racially/ethnically diverse populations of men and women protected by the U.S. Environmental Protection Agency under the Clean Air Act.

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