title: Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population.
abstract: Susceptibility to coronary heart disease (CHD) has long been known to exhibit familial aggregation, with heritability estimated to be greater than 50%. The French Canadian population of the Saguenay-Lac Saint-Jean region of Quebec, Canada is descended from a founder population that settled this region 300-400 years ago and this may provide increased power to detect genes contributing to complex traits such as CHD. Probands with early-onset CHD, defined by angiographically determined coronary stenosis, and their relatives were recruited from this population (average sibship size of 6.4). Linkage analysis was performed following a genome-wide microsatellite marker scan on 42 families with 284 individuals. Nonparametric linkage (NPL) analysis provided suggestive evidence for a CHD susceptibility locus on chromosome 8 with an NPL score of 3.14 (P=0.001) at D8S1106. Linkage to this locus was verified by fine mapping in an enlarged sample of 50 families with 320 individuals. This analysis provided evidence of linkage at D8S552 (NPL score=3.53, P=0.0003), a marker that maps to the same location as D8S1106. Candidate genes in this region, including macrophage scavenger receptor 1, farnesyl-diphosphate farnesyltransferase 1, fibrinogen-like 1, and GATA-binding protein 4, were resequenced in all coding exons in both affected and unaffected individuals. Association studies with variants in these and five other genes did not identify a disease-associated mutation. In conclusion, a genome-wide scan and additional fine mapping provide evidence for a locus on chromosome 8 that contributes to CHD in a French Canadian population.
authors.affiliation: McGill University Health Centre, Montréal, Québec, Canada. jamie.engert@mcgill.ca
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Janet
authors.initials: J
authors.lastname: Faith
authors.forename: Diane
authors.initials: D
authors.lastname: Brisson
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.forename: Carl G
authors.initials: CG
authors.lastname: Brewer
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Corinne
authors.initials: C
authors.lastname: Darmond-Zwaig
authors.forename: Yannick
authors.initials: Y
authors.lastname: Renaud
authors.forename: Carole
authors.initials: C
authors.lastname: Doré
authors.forename: Swneke D
authors.initials: SD
authors.lastname: Bailey
authors.forename: Andrei
authors.initials: A
authors.lastname: Verner
authors.forename: Gérald
authors.initials: G
authors.lastname: Tremblay
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Christine
authors.initials: C
authors.lastname: Bétard
authors.forename: Jill
authors.initials: J
authors.lastname: Platko
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005602:France / Q000208:ethnology; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011792:Quebec