Genome-wide Association Study of Cardiovascular Traits in 6142 Sardinians

National Institute On Aging

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Abstract

1) Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We performed our GWAS to identify single nucleotide polymorphisms (SNPs) associated with PWV and identified the nonsynonymous SNP, rs3742207 in exon 45 of the COL4A1 gene on chromosome 13 (p=7.08x10-7) in Sardinian cohort (4,221 individuals) using Affymetrix 500K chip. This signal was successfully replicated in Amish cohort (combined p=5.16x10-8). Additional genotyping was performed in SardiNIA cohort with Affymetrix 6.0 array confirmed previously found genetic association. Six SNPs flanking exon 45 within 1200 bases were in high linkage disequilibrium (r2=0.994) with rs3742207. In search of a causal variant we sequenced the COL4A1 gene for exons 39 - 50 in nearly close intronic regions, in 20 subjects with high and 20 subjects with low PWV. Sequencing did not reveal new variants in this region but confirmed the presence of 8 previously known SNPs. Collagen type 4 is one of the major structural components of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness. Recently SardiNIA have joined international consortium Aorta-Gen (24000 individuals) in order to have finer mapping and identify new loci associated with PWV. Has been identified new locus on desert region of Chromosome 14 in the conserved core of the BCL11B gene enhancer that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, P = 7.4 x 10-11;replication P = 1.4 x 10-6;meta-analysis P = 3.1 x 10-15). Further elucidation of the role that this novel locus plays in aortic stiffness may facilitate the development of specific therapeutic interventions that reduce or prevent aortic stiffening and related cardiovascular disease events. 2) The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify new underlying common genetic variation associated with PR interval, SardiNIA joined new giant consortium PRIMA for meta-analysis of GWAS results from 33 community-based studies of European-ancestry individuals (N80,000). First meta-analysis identified 31 associated loci including 8 known associated with PR-interval modulation. 3) We demonstrated an association of QT interval prolongation with phospholamban (PLN) locus on chromosomal DNA. Also, were demonstrated, that QT interval for people with this allele was 1.809 ms larger in older individuals than in younger. We performed ECG measurements on PLN KO mice to investigate whether the PLN gene is indeed associated with QT interval prolongation with age. Also we test hypothesis that cardiac response on drugs with effect on QT interval prolongation will be different for wild type and PLN KO animals. Understanding of intrinsic mechanisms of PLN association with QT interval prolongation may lead to effective interventions that could prevent such condition.