Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy
TIMI Study Group; Department of Molecular Genetics and Microbiology
Life Sciences | Medicine and Health Sciences
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; P(interaction)=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) (P(interaction)=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.
DOI of Published Version
Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):562-7. Epub 2008 Jan 3. Link to article on publisher's site
Arteriosclerosis, thrombosis, and vascular biology
Sabatine MS, Ploughman LM, Simonsen KL, Iakoubova OA, Kirchgessner TG, Ranade K, Tsuchihashi Z, Zerba KE, Long DU, Tong CH, Packard CJ, Pfeffer MA, Devlin JJ, Shepherd J, Campos H, Sacks FM, Braunwald E. (2008). Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy. GSBS Student Publications. https://doi.org/10.1161/ATVBAHA.107.156653. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1427