Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17.
Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size lambda(sib) > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies.
Farrall
Martin
M
Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
Green
Fiona R
FR
Peden
John F
JF
Olsson
Per G
PG
Clarke
Robert
R
Hellenius
Mai-Lis
ML
Rust
Stephan
S
Lagercrantz
Jacob
J
Franzosi
Maria Grazia
MG
Schulte
Helmut
H
Carey
Alisoun
A
Olsson
Gunnar
G
Assmann
Gerd
G
Tognoni
Gianni
G
Collins
Rory
R
Hamsten
Anders
A
Watkins
Hugh
H
D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D003324:Coronary Artery Disease / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008126:Lod Score; D018895:Microsatellite Repeats; D010641:Phenotype