A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI

Rong Yang, Lin Li, Sara Bretschger Seidelmann, Gong Qing Shen, Sonia Sharma, Shaoqi Rao, Kalil G. Abdullah, Kenneth G. MacKinlay, Robert C. Elston, Qiuyun Chen, Eric J. Topol, Qing Kenneth Wang

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Abstract

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 × 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.

Original languageEnglish (US)
Pages (from-to)1442-1451
Number of pages10
JournalJournal of lipid research
Volume51
Issue number6
DOIs
Publication statusPublished - Jun 1 2010
Externally publishedYes

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Keywords

  • Coronary artery disease
  • Genetics
  • Genome-wide scan
  • High density lipoprotein cholesterol
  • Linkage
  • LIPC gene
  • Myocardial infarction
  • Quantitative trait locus
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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