Article

European Journal of Human Genetics (2010) 18, 342–347; doi:10.1038/ejhg.2009.157; published online 21 October 2009

Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects

Zari Dastani1,2, Päivi Pajukanta3, Michel Marcil1, Nicholas Rudzicz4, Isabelle Ruel1, Swneke D Bailey2, Jenny C Lee3, Mathieu Lemire5,9, Janet Faith5, Jill Platko6,10, John Rioux6,11, Thomas J Hudson2,5,7,9, Daniel Gaudet8, James C Engert2,7 and Jacques Genest1,2,7

  1. 1Cardiovascular Genetics Laboratory, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada
  2. 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  3. 3Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA
  4. 4Department of Computer Science, McGill University, Montreal, Quebec, Canada
  5. 5McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
  6. 6Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA
  7. 7Department of Medicine, McGill University, Montreal, Quebec, Canada
  8. 8Dyslipidemia, Diabetes and Atherosclerosis Group and Community Genomics Research Center, Université de Montréal and Complexe hospitalier de la Sagamie, Chicoutimi, Quebec, Canada

Correspondence: Dr JC Engert, Departments of Medicine and Human Genetics, McGill University, Royal Victoria Hospital, H7.30, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Tel: +1 514 934-1934; Fax +1 514 843-2843; E-mail: jamie.engert@mcgill.ca

9Present address: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

10Present address: PHT Corporation, 500 Rutherford Avenue, Boston, MA, USA;

11Present address: Broad Institute of MIT and Harvard, Cambridge, MA, USA; Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.

Received 29 January 2009; Revised 24 June 2009; Accepted 10 August 2009; Published online 21 October 2009.

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Abstract

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 98cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18Mb) region, which was further reduced to 6.6Mb 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.

Keywords:

HDL-C, family study, complex traits, coronary heart disease, gene identification