Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy
TIMI Study Group; Department of Molecular Genetics and Microbiology
Medical Subject Headings
Adult; Age Factors; Analysis of Variance; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Genetic Variation; Genotype; Humans; Male; Matrix Metalloproteinases; Middle Aged; *Polymorphism, Genetic; Pravastatin; Predictive Value of Tests; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Survival Analysis; Treatment Outcome
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.
Rights and Permissions
Citation: Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):562-7. Epub 2008 Jan 3. Link to article on publisher's site
DOI of Published Version
Arteriosclerosis, thrombosis, and vascular biology
Sabatine, Marc S.; Ploughman, Lynn M.; Simonsen, Katy L.; Iakoubova, Olga A.; Kirchgessner, Todd G.; Ranade, Koustubh; Tsuchihashi, Zenta; Zerba, Kim E.; Long, Diane U.; Tong, Carmen H.; Packard, Christopher J.; Pfeffer, Marc A.; Devlin, James J.; Shepherd, James; Campos, Hannia; Sacks, Frank M.; and Braunwald, Eugene, "Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy" (2008). GSBS Student Publications. 1427.