Publication
Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5
Publisher:
Springer Science and Business Media LLC
Date:
27-02-2012
DOI:
10.1186/1471-2156-13-12
Abstract: Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 in iduals from the CATHGEN biorepository of patients undergoing cardiac catheterization 254 families (N = 827 in iduals) from the GENECARD familial study of early-onset CAD and 162 aorta s les harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all s les using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL GENECARD) and logistic regression (CATHGEN and aortas). We identified four genes with SNPs that showed the strongest and most consistent associations with LDL-C and CAD: EBF1 , PPP2R2B , SPOCK1 , and PRELID2 . The most significant results for association of SNPs with LDL-C were: EBF1 , rs6865969, p = 0.01 PPP2R2B , rs2125443, p = 0.005 SPOCK1 , rs17600115, p = 0.003 and PRELID2 , rs10074645, p = 0.0002). The most significant results for CAD were EBF1 , rs6865969, p = 0.007 PPP2R2B , rs7736604, p = 0.0003 SPOCK1 , rs17170899, p = 0.004 and PRELID2 , rs7713855, p = 0.003. Using an intermediate disease-related quantitative trait of LDL-C we have identified four novel CAD genes, EBF1 , PRELID2 , SPOCK1 , and PPP2R2B . These four genes should be further examined in future functional studies as candidate susceptibility loci for cardiovascular disease mediated through LDL-cholesterol pathways.
0000-0003-3584-6148