title: Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Human Genetics, Duke University, 905 S, LaSalle Street, Duke Univeristy Medical Center, Durham, NC 27710, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nolan
authors.forename: Beth
authors.initials: B
authors.lastname: Sutton
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sebek
authors.forename: Elaine
authors.initials: E
authors.lastname: Dowdy
authors.forename: David
authors.initials: D
authors.lastname: Crosslin
authors.forename: David
authors.initials: D
authors.lastname: Crossman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Sketch
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.forename: David
authors.initials: D
authors.lastname: Seo
authors.forename: Pascal
authors.initials: P
authors.lastname: Goldschmidt-Clermont
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
mesh_terms: D050197:Atherosclerosis / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods*; D002895:Chromosomes, Human, Pair 5; D003324:Coronary Artery Disease / Q000235:genetics*; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D015810:Linkage Disequilibrium; D008055:Lipids / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable
chemical_list: D008078:Cholesterol, LDL; D008055:Lipids