Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population.
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.
Engert
James C
JC
McGill University Health Centre, Montréal, Québec, Canada. jamie.engert@mcgill.ca
Lemire
Mathieu
M
Faith
Janet
J
Brisson
Diane
D
Fujiwara
T Mary
TM
Roslin
Nicole M
NM
Brewer
Carl G
CG
Montpetit
Alexandre
A
Darmond-Zwaig
Corinne
C
Renaud
Yannick
Y
Doré
Carole
C
Bailey
Swneke D
SD
Verner
Andrei
A
Tremblay
Gérald
G
St-Pierre
Julie
J
Bétard
Christine
C
Platko
Jill
J
Rioux
John D
JD
Morgan
Kenneth
K
Hudson
Thomas J
TJ
Gaudet
Daniel
D
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