TY - JOUR
T1 - Evidence for a gene influencing high-density lipoprotein cholesterol on chromosome 4q31.21
AU - Dastani, Zari
AU - Quiogue, Leigh
AU - Plaisier, Christopher
AU - Engert, James C.
AU - Marcil, Michel
AU - Genest, Jacques
AU - Pajukanta, Päivi
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
KW - Complex trait
KW - Coronary heart disease
KW - Family study
KW - Gene identification
KW - High-density lipoprotein cholesterol
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U2 - 10.1161/01.ATV.0000198243.83781.a3
DO - 10.1161/01.ATV.0000198243.83781.a3
M3 - Article
C2 - 16322534
AN - SCOPUS:33644870712
SN - 1079-5642
VL - 26
SP - 392
EP - 397
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 2
ER -