Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.
Dastani
Zari
Z
Cardiovascular Genetics Laboratory, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada.
Pajukanta
Päivi
P
Marcil
Michel
M
Rudzicz
Nicholas
N
Ruel
Isabelle
I
Bailey
Swneke D
SD
Lee
Jenny C
JC
Lemire
Mathieu
M
Faith
Janet
J
Platko
Jill
J
Rioux
John
J
Hudson
Thomas J
TJ
Gaudet
Daniel
D
Engert
James C
JC
Genest
Jacques
J
D002170:Canada; D008076:Cholesterol, HDL / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005602:France; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D020161:Physical Chromosome Mapping; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
D008076:Cholesterol, HDL; D012333:RNA, Messenger