A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI.
Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 x 10(-4)). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.
Yang
Rong
R
Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Center for Cardiovascular Genetics, Cleveland, OH 44195, USA.
Li
Lin
L
Seidelmann
Sara Bretschger
SB
Shen
Gong-Qing
GQ
Sharma
Sonia
S
Rao
Shaoqi
S
Abdullah
Kalil G
KG
Mackinlay
Kenneth G
KG
Elston
Robert C
RC
Chen
Qiuyun
Q
Topol
Eric J
EJ
Wang
Qing Kenneth
QK
D000367:Age Factors; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D003001:Cloning, Molecular; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012737:Sex Factors
D008076:Cholesterol, HDL