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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2030.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease

May M. Luke; John P. Kane; Dongming M. Liu; Charles M. Rowland; Dov Shiffman; June Cassano; Joseph J. Catanese; Clive R. Pullinger; Diane U. Leong; Andre R. Arellano; Carmen H. Tong; Irina Movsesyan; Josephina Naya-Vigne; Curtis Noordhof; Nicole T. Feric; Mary J. Malloy; Eric J. Topol; Marlys L. Koschinsky; James J. Devlin; Stephen G. Ellis

From Celera (M.M.L., D.M.L., C.M.R., D.S., J.J.C., D.U.L., A.R.A., C.H.T., J.J.D.), Alameda, Calif; the Cardiovascular Research Institute (J.P.K., C.R.P., I.M., J.N.-V., M.J.M.), UCSF, San Francisco, Calif; The Cleveland Clinic Foundation, Department of Cardiovascular Medicine (J.C., E.J.T., S.G.E.), Cleveland, Ohio; the Department of Biochemistry (C.N., N.T.F., M.L.K.), Queen’s University, Kingston, Ontario, Canada; and The Scripps Research Institute (E.J.T.), La Jolla, Calif.

Correspondence to May M. Luke, Celera, 1401 Harbor Bay Parkway, Alameda, CA 94502. E-mail may.luke{at}celera.com

Objectives— The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD).

Methods and Results— We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003).

Conclusions— The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.

A SNP in the protease-like domain of the LPA gene (I4399M, rs3798220) is associated with severe coronary artery disease and plasma lipoprotein(a) levels.

Key Words: coronary arteriosclerosis • genetics • single nucleotide polymorphism • lipoprotein(a) • risk factors

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