Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 81, Issue 4, 780-791, 1 October 2007
doi:10.1086/521581
Article
An LRP8 Variant Is Associated with Familial and Premature Coronary Artery Disease and Myocardial Infarction
Gong-Qing Shena, c, f, Lin Lia, c, f, Domenico Girellii, Sara B. Seidelmanna, c, f, Shaoqi Raoc, f, Chun Fana, c, f, Jeong Euy Parkj, Quansheng Xia, c, f, Jing Lig, Ying Hua, c, f, Oliviero Olivierii, Kandice Marchantd, John Barnarde, Roberto Corrocheri, Robert Elstonh, June Cassanoa, c, f, Susan Hendersona, c, f, Stanley L. Hazenb, Edward F. Plowa, c, f, Eric J. Topol*, k and Qing K. Wang*, a, c, f, 
, 
a From the Department of Molecular Cardiology, Case Western Reserve University, Cleveland
b Department of Cell Biology, Case Western Reserve University, Cleveland
c Lerner Research Institute, Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Case Western Reserve University, Cleveland
d Department of Clinical Pathology, Case Western Reserve University, Cleveland
e Department of Quantitative Health Sciences, Case Western Reserve University, Cleveland
f Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Case Western Reserve University, Cleveland
g Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland
h Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland
i Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
j Samsung Medical Center, Sungkyunkwan University, Seoul
k and Scripps Genomic Medicine, The Scripps Research Institute, La Jolla, CA
Address for correspondence and reprints: Dr. Qing K. Wang, Center for Cardiovascular Genetics/NE40, Cleveland Clinic, Cleveland, OH 44195* These two authors contributed equally to this work.
Abstract
Our previous genomewide linkage scan of 428 nuclear families (GeneQuest) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on chromosome 1p34-36. We analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from the GeneQuest families (381 cases) and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. Three additional white populations were used for follow-up replication studies: another independent cohort of CAD- and/or MI-affected families (GeneQuest II: 441 individuals from 22 pedigrees), an Italian cohort with familial MI (248 cases) and 308 Italian controls, and a separate Cleveland GeneBank cohort with sporadic MI (1,231 cases) and 560 controls. The association was significantly replicated in two independent populations with a family history of CAD and/or MI, the GeneQuest II family-based replication cohort and the Italian cohort, but not in the population with sporadic disease. The R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase by oxidized low-density lipoprotein. This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI.
Article Information
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