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.
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).
Pare
Guillaume
G
McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
Serre
David
D
Brisson
Diane
D
Anand
Sonia S
SS
Montpetit
Alexandre
A
Tremblay
Gerald
G
Engert
James C
JC
Hudson
Thomas J
TJ
Gaudet
Daniel
D
D052242:Adiponectin / Q000097:blood; D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood*; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D017931:DNA Primers; D019332:Endothelin-1 / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011792:Quebec; D012737:Sex Factors
D052242:Adiponectin; D008076:Cholesterol, HDL; D017931:DNA Primers; D019332:Endothelin-1