on January 3, 2008
Published online before print January 3, 2008, doi: 10.1161/ATVBAHA.107.156653
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Submitted on July 22, 2007
Accepted on December 11, 2007
Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy
Marc S. Sabatine *;
From the TIMI Study Group, Cardiovascular Division (M.S.S., M.A.P., E.A.B.), Brigham & Women’s Hospital, Harvard Medical School, Boston, Mass; Pharmaceutical Research Institute (L.P., K.L.S., T.G.K., K.R., Z.T., K.E.Z., N.C.D.), Bristol-Myers Squibb, Princeton, NJ; the Department of Statistics (K.L.S.), Purdue University, West Lafayette, Ind; Celera (O.A.I., D.U.L., C.H.T., J.J.D.), Alameda, Calif; University of Glasgow and Royal Infirmary (C.J.P., J.S.), Glasgow, UK; and the Harvard School of Public Health (H.C., F.M.S.), Boston, Mass.
* To whom correspondence should be addressed. E-mail: msabatine{at}partners.org.
Objective—The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin therapy in 2 independent cohorts.
Methods and Results—The frequency of the ADAMTS1 227Pro minor allele was 0.24 in 2421 male subjects from CARE, a randomized trial of pravastatin versus placebo. In the placebo arm, homozygotes (6.3% of study population) had a significantly increased risk of fatal coronary disease or nonfatal myocardial infarction (D/MI) compared with noncarriers (OR 2.12, 95% CI 1.07 to 4.19, P=0.03), and in the entire study the benefit of pravastatin in reducing the risk of D/MI was greater in these subjects (OR 0.21, 95% CI 0.06 to 0.69) than in heterozygotes (OR 0.74, 95% CI 0.48 to 1.14) or noncarriers (OR 0.99, 95% CI 0.68 to 1.42; Pinteraction=0.044). Results were tested in 1565 male subjects from WOSCOPS, also a randomized trial of pravastatin versus placebo. Similar to the results in CARE, in the placebo arm subjects homozygous for the minor allele were at increased risk of D/MI (OR 1.72, P=0.052) and in the entire study the benefit of pravastatin in reducing D/MI was greater in these subjects (OR 0.24, 95% CI 0.09 to 0.68) than in heterozygotes (OR 0.73, 95% CI 0.48 to 1.11) or noncarriers (OR 0.65, 95% CI 0.20 to 2.09) (Pinteraction=0.029).
Conclusions—In men not on pravastatin, those homozygous for the 227Pro allele of ADAMTS1 have a nearly 2-fold increased risk of coronary heart disease events compared with noncarriers. In this high-risk group, treatment with pravastatin is highly efficacious, reducing the odds of fatal coronary disease or nonfatal MI by approximately 75%, as compared with 25% in noncarriers or heterozygotes.
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