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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:392.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Evidence for a Gene Influencing High-Density Lipoprotein Cholesterol on Chromosome 4q31.21

Zari Dastani; Leigh Quiogue; Christopher Plaisier; James C. Engert; Michel Marcil; Jacques Genest; Päivi Pajukanta

From the Departments of Medicine and Human Genetics (Z.D., J.C.E., J.G.), McGill University, Montreal, Canada; Department of Human Genetics (L.Q., C.P., P.P.), David Geffen School of Medicine, University of California, Los Angeles; Division of Cardiology (M.M.), McGill University, Montreal, Canada.

Correspondence to Päivi Pajukanta, MD, PhD, Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Center, Room 6335A, 695 Charles E. Young Dr S, Los Angeles, CA 90095-7088. E-mail ppajukanta{at}mednet.ucla.edu

Objective— A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary atherosclerosis. To identify novel genes regulating plasma HDL-C levels, we investigated 13 multigenerational French Canadian families with an average of 12 affected individuals per family for genome-wide signals, which we subsequently fine mapped.

Methods and Results— We genotyped a total of 362 individuals, including 151 affected subjects for 485 autosomal microsatellite markers. In parametric 2-point linkage analyses, the highest 2-point logarithm of odds (lod) score of 4.6 was observed with marker D4S424 on chromosome 4q31.21 (at 142 Mb). The multipoint analysis of this region resulted in a lod score of 3.8 and a lod –1 region of 12.2 cM, containing 40 known genes. The results were obtained by allowing for genetic heterogeneity among these extended pedigrees, and 50% of families were linked to this region with the highest single-pedigree lod score being 3.6. We further restricted the linked region from 12.2 to 2.9 cM (2.37 Mb) by genotyping 15 additional markers in the 3 families with the highest lod scores. We sequenced 4 genes with a likely role in lipid metabolism as well as 2 genes residing directly under the linkage peak but found no evidence for a causative variant. None of the genes residing in the significantly restricted 2.37-Mb region has been associated previously with HDL-C metabolism.

Conclusion— This study provides significant evidence for a gene influencing HDL-C on chromosome 4q31.21.

To identify novel genes regulating plasma HDL-C levels, we analyzed multigenerational French Canadian families for genome-wide signals, which we subsequently fine mapped. We identified a 2.37-Mb region on chromosome 4q31.21 likely containing a gene influencing HDL-C levels.

Key Words: high-density lipoprotein cholesterol • family study • complex trait • coronary heart disease • gene identification