Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 4, 673-682, 1 April 2007
doi:10.1086/513286
Article
Genetic Analysis of 103 Candidate Genes for Coronary Artery Disease and Associated Phenotypes in a Founder Population Reveals a New Association between Endothelin-1 and High-Density Lipoprotein Cholesterol
Guillaume Paréa, b, David Serrea, b, Diane Brissonc, Sonia S. Anandd, Alexandre Montpetita, b, Gérald Tremblayc, James C. Engertb, Thomas J. Hudsona, b, e, 
, 
and Daniel Gaudetc
a McGill University and Genome Quebec Innovation Centre, Canada
b Department of Human Genetics and Medicine, Faculty of Medicine, McGill University, Montreal
c Montreal University Community Genomic Medicine Center and Lipid Clinic, Department of Medicine, Université de Montréal, Chicoutimi Hospital, Chicoutimi, Canada
d Department of Medicine, McMaster University, Hamilton, Ontario
e Ontario Institute for Cancer Research, Toronto
Address for correspondence and reprints: Dr. Thomas J. Hudson, Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 500, Toronto, Ontario, Canada M5G 1L7Abstract
Coronary artery disease (CAD) is a major health concern in both developed and developing countries. With a heritability estimated at ∼50%, there is a strong rationale to better define the genetic contribution to CAD. This project involves the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 case and control subjects from the Saguenay Lac St-Jean region of northeastern Quebec, with the use of 1,536 single-nucleotide polymorphisms (SNPs) in 103 candidate genes for CAD. By use of clusters of SNPs to generate multiallelic haplotypes at candidate loci for segregation studies within families, suggestive linkage for high-density lipoprotein (HDL) cholesterol is observed on chromosome 1p36.22. Furthermore, several associations that remain significant after Bonferroni correction are observed with lipoprotein-related traits as well as plasma concentrations of adiponectin. Of note, HDL cholesterol levels are associated with an amino acid substitution (lysine/asparagine) at codon 198 (rs5370) of endothelin-1 (EDN1) in a sex-specific manner, as well as with a SNP (rs2292318) located 7.7 kb upstream of lecithin cholesterol acyl-transferase (LCAT). Whereas the other observed associations are described in the current literature, these two are new. Using an independent validation sample of 806 individuals, we confirm the EDN1 association (P<.005), whereas the LCAT association was nonsignificant (P=.12).
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