Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5

BMC Genetics

Svati H Shah¹  Elizabeth R Hauser¹  Simon G Gregory¹  William E Kraus¹  Pascal Goldschmidt-Clermont²  David Seo²  Christopher B Granger¹  Michael H Sketch¹  David Crossman³  David Crosslin⁴  Elaine Dowdy⁴  Jacqueline Sebek⁴  Jessica Johnson⁴  Carol Haynes⁴  Beth Sutton⁴  Daniel K Nolan⁴ 

[1] Department of Medicine, Duke University, 2301 Erwin Road, Durham NC, 27710, USA;Miller School of Medicine, University of Miami, 1601 Northwest 12th Avenue, Miami FL, 33136, USA;University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK;Center for Human Genetics, Duke University, 905 S. LaSalle Street, Duke Univeristy Medical Center, Durham NC, 27710, USA

关键词: Fine Mapping;    Linkage;    Intermediate Phenotype;    Positional Cloning;    Cardiovascular Disease;   

Others  :  1122517
DOI  :  10.1186/1471-2156-13-12

 received in 2011-05-05, accepted in 2012-02-27,  发布年份 2012

【 摘 要 】

Background

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 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples 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 samples 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).

Results

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.

Conclusion

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.

【 授权许可】

   
2012 Nolan et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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Figure 3.

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