Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy.

Abstract

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.

• Authors: Marc S Sabatine, Lynn Ploughman, Katy L Simonsen, Olga A Iakoubova, Todd G Kirchgessner, Koustubh Ranade, Zenta Tsuchihashi, Kim E Zerba, Diane U Long, Carmen H Tong, Christopher J Packard, Marc A Pfeffer, James J Devlin, James Shepherd, Hannia Campos, Frank M Sacks, Eugene Braunwald
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 3 Pg. 562-7 (Mar 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18174457 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Matrix Metalloproteinases
• Pravastatin

Topics

• Adult
• Age Factors
• Analysis of Variance
• Coronary Disease (drug therapy, genetics, mortality)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Follow-Up Studies
• Genetic Variation
• Genotype
• Humans
• Male
• Matrix Metalloproteinases (genetics, metabolism)
• Middle Aged
• Polymorphism, Genetic
• Pravastatin (therapeutic use)
• Predictive Value of Tests
• Probability
• Reference Values
• Risk Assessment
• Severity of Illness Index
• Survival Analysis
• Treatment Outcome