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 > or =0.10, genotype call rate > or =0.80, and Hardy-Weinberg equilibrium p > or = 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 webcite. 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 (NOLA1, p = 2.74*10(-6)); exercise systolic blood pressure, rs2553268 (WRN, p = 6.3*10(-6)); BA baseline flow, rs3814219 (OBFC1, 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.