on June 14, 2007
Published online before print June 14, 2007, doi: 10.1161/ATVBAHA.107.141291
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Submitted on February 5, 2007
Accepted on May 23, 2007
A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease
May M. Luke *;
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.
* To whom correspondence should be addressed. 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.
Key words: coronary arteriosclerosis • genetics • single nucleotide polymorphism • lipoprotein(a) • risk factors