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

Publication ,  Journal Article
Nolan, DK; Sutton, B; Haynes, C; Johnson, J; Sebek, J; Dowdy, E; Crosslin, D; Crossman, D; Sketch, MH; Granger, CB; Seo, D; Kraus, WE ...
Published in: BMC Genet
February 27, 2012

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.

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Published In

BMC Genet

DOI

EISSN

1471-2156

Publication Date

February 27, 2012

Volume

13

Start / End Page

12

Location

England

Related Subject Headings

  • Quantitative Trait, Heritable
  • Polymorphism, Single Nucleotide
  • Lipids
  • Linkage Disequilibrium
  • Humans
  • Genetics & Heredity
  • Genetic Linkage
  • Genetic Association Studies
  • Coronary Artery Disease
  • Chromosomes, Human, Pair 5
 

Citation

APA
Chicago
ICMJE
MLA
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Nolan, D. K., Sutton, B., Haynes, C., Johnson, J., Sebek, J., Dowdy, E., … Shah, S. H. (2012). Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5. BMC Genet, 13, 12. https://doi.org/10.1186/1471-2156-13-12
Nolan, Daniel K., Beth Sutton, Carol Haynes, Jessica Johnson, Jacqueline Sebek, Elaine Dowdy, David Crosslin, et al. “Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5.BMC Genet 13 (February 27, 2012): 12. https://doi.org/10.1186/1471-2156-13-12.
Nolan DK, Sutton B, Haynes C, Johnson J, Sebek J, Dowdy E, et al. Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5. BMC Genet. 2012 Feb 27;13:12.
Nolan, Daniel K., et al. “Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5.BMC Genet, vol. 13, Feb. 2012, p. 12. Pubmed, doi:10.1186/1471-2156-13-12.
Nolan DK, Sutton B, Haynes C, Johnson J, Sebek J, Dowdy E, Crosslin D, Crossman D, Sketch MH, Granger CB, Seo D, Goldschmidt-Clermont P, Kraus WE, Gregory SG, Hauser ER, Shah SH. Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5. BMC Genet. 2012 Feb 27;13:12.
Journal cover image

Published In

BMC Genet

DOI

EISSN

1471-2156

Publication Date

February 27, 2012

Volume

13

Start / End Page

12

Location

England

Related Subject Headings

  • Quantitative Trait, Heritable
  • Polymorphism, Single Nucleotide
  • Lipids
  • Linkage Disequilibrium
  • Humans
  • Genetics & Heredity
  • Genetic Linkage
  • Genetic Association Studies
  • Coronary Artery Disease
  • Chromosomes, Human, Pair 5