Evidence for a gene influencing high-density lipoprotein cholesterol on chromosome 4q31.21.
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.


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 approximately 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 approximately 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.


CONCLUSIONS
This study provides significant evidence for a gene influencing HDL-C on chromosome 4q31.21.
Dastani
Zari
Z
Department of Medicine, McGill University, Montreal, Canada.
Quiogue
Leigh
L
Plaisier
Christopher
C
Engert
James C
JC
Marcil
Michel
M
Genest
Jacques
J
Pajukanta
Päivi
P
D002170:Canada; D008076:Cholesterol, HDL / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D003324:Coronary Artery Disease / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats
D008076:Cholesterol, HDL; D005819:Genetic Markers