title: 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.
  
  
  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.affiliation: TIMI Study Group, Cardiovascular Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mssabatine@partners.org
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.forename: Lynn
authors.initials: L
authors.lastname: Ploughman
authors.forename: Katy L
authors.initials: KL
authors.lastname: Simonsen
authors.forename: Olga A
authors.initials: OA
authors.lastname: Iakoubova
authors.forename: Todd G
authors.initials: TG
authors.lastname: Kirchgessner
authors.forename: Koustubh
authors.initials: K
authors.lastname: Ranade
authors.forename: Zenta
authors.initials: Z
authors.lastname: Tsuchihashi
authors.forename: Kim E
authors.initials: KE
authors.lastname: Zerba
authors.forename: Diane U
authors.initials: DU
authors.lastname: Long
authors.forename: Carmen H
authors.initials: CH
authors.lastname: Tong
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Packard
authors.forename: Marc A
authors.initials: MA
authors.lastname: Pfeffer
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.forename: James
authors.initials: J
authors.lastname: Shepherd
authors.forename: Hannia
authors.initials: H
authors.lastname: Campos
authors.forename: Frank M
authors.initials: FM
authors.lastname: Sacks
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D003327:Coronary Disease / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D020782:Matrix Metalloproteinases; D017035:Pravastatin