Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

Background: Echocardiographic left ventricular ( LV) measurements, exercise responses to standardized treadmill test ( ETT) and brachial artery ( BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study ( GWAS) in the community-based Framingham Heart Study. Methods: We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures ( single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures ( single exam) included vessel diameter, flow-mediated dilation ( FMD), and baseline and hyperemic flow responses. Generalized estimating equations ( GEE), family-based association tests ( FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs ( Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency >= 0.10, genotype call rate >= 0.80, and Hardy-Weinberg equilibrium p >= 0.001. Results: We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. We confirmed modest-to-strong heritabilities ( estimates 0.30-0.52) for several Echo, ETT and BA function traits. Overall, p < 10(-5) in either GEE or FBAT models were observed for 21 SNPs ( nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were ( GEE results): LV diastolic dimension, rs1379659 ( SLIT2, p = 1.17* 10(-7)); LV systolic dimension, rs10504543 ( KCNB2, p = 5.18* 10(-6)); LV mass, rs10498091 ( p = 5.68* 10(-6)); Left atrial size, rs1935881 ( FAM5C, p = 6.56* 10(-6)); exercise heart rate, rs6847149 ( NOLAI, p = 2.74* 10(-6)); exercise systolic blood pressure, rs2553268 ( WRN, p = 6.3* 10(-6)); BA baseline flow, rs3814219 ( OBFCI, 9.48* 10(-7)), and FMD, rs4148686 ( CFTR, p = 1.13* 10(-5)). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass ( 4.38; chromosome 5); the 1.5 LOD support interval included NRG2. Conclusion: In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.