PMID- 21183746
OWN - NLM
STAT- MEDLINE
DCOM- 20110302
LR  - 20211020
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Print)
IS  - 0039-2499 (Linking)
VI  - 42
IP  - 2
DP  - 2011 Feb
TI  - Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in 
      relation to antihypertensive treatment: the genetics of hypertension associated 
      treatment study.
PG  - 330-5
LID - 10.1161/STROKEAHA.110.593798 [doi]
AB  - BACKGROUND AND PURPOSE: Atherothrombotic diseases including stroke share a common 
      etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic 
      component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial 
      matrix composition and is a candidate gene for atherothrombosis. A common 
      polymorphism of MMP3 alters expression levels and affects atherosclerotic 
      progression and plaque stability. As part of the Genetics of Hypertension 
      Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering 
      to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to 
      determine its association with stroke and determine whether it modifies clinical 
      outcome response to blood pressure-lowering drugs. METHODS: The effect of the 
      MMP3 5A/6A polymorphism on stroke rates was examined by using 
      multivariate-adjusted Cox regression models, including a test for interactions 
      between genotype and antihypertensive drug class. RESULTS: Compared with 
      participants treated with chlorthalidone with the 6A/6A genotype, individuals 
      with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard 
      ratio=1.32; 95% CI, 1.08 to 1.61; P=0.007) and 5A/6A individuals taking 
      lisinopril had lower stroke rates (hazard ratio(interaction)=0.74; 95% CI, 0.53 
      to 1.04; P(interaction)=0.08), whereas 5A/5A individuals taking lisinopril had 
      the lowest stroke rate (hazard ratio(interaction)=0.51; 95% CI, 0.31 to 0.85; 
      P(interaction)=0.009). There were no pharmacogenetic differences in stroke rate 
      by genotype in patients taking amlodipine or doxazosin vs chlorthalidone. 
      CONCLUSIONS: The MMP3 6A/6A genotype is associated with an increased risk of 
      stroke in hypertensive subjects taking lisinopril compared with patients treated 
      with chlorthalidone, whereas a protective effect was found for 5A/5A individuals 
      treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a 
      useful tool to select optimal antihypertensive therapy if this finding is 
      replicated. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. 
      Unique identifier: NCT00563901.
FAU - Sherva, Richard
AU  - Sherva R
AD  - Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 
      32594, USA.
FAU - Ford, Charles E
AU  - Ford CE
FAU - Eckfeldt, John H
AU  - Eckfeldt JH
FAU - Davis, Barry R
AU  - Davis BR
FAU - Boerwinkle, Eric
AU  - Boerwinkle E
FAU - Arnett, Donna K
AU  - Arnett DK
LA  - eng
SI  - ClinicalTrials.gov/NCT00563901
GR  - HL63082/HL/NHLBI NIH HHS/United States
GR  - R01 HL083498/HL/NHLBI NIH HHS/United States
GR  - N01-HC-35130/HC/NHLBI NIH HHS/United States
GR  - N01HC35130/HL/NHLBI NIH HHS/United States
GR  - R01 HL063082/HL/NHLBI NIH HHS/United States
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
DEP - 20101223
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
RN  - 0 (Antihypertensive Agents)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Aged
MH  - Antihypertensive Agents/adverse effects/*therapeutic use
MH  - Double-Blind Method
MH  - Female
MH  - Follow-Up Studies
MH  - Genetic Predisposition to Disease/genetics
MH  - Humans
MH  - Hypertension/complications/*drug therapy/*genetics
MH  - Male
MH  - Matrix Metalloproteinase 3/*genetics/physiology
MH  - Middle Aged
MH  - Polymorphism, Genetic/*genetics
MH  - Prospective Studies
MH  - Risk Factors
MH  - Stroke/chemically induced/etiology/*genetics
MH  - Treatment Outcome
PMC - PMC3859235
MID - NIHMS499879
COIS- Conflicts of Interest/Disclosures: Authors report having no conflicts of interest 
      to disclose.
EDAT- 2010/12/25 06:00
MHDA- 2011/03/03 06:00
PMCR- 2013/12/11
CRDT- 2010/12/25 06:00
PHST- 2010/12/25 06:00 [entrez]
PHST- 2010/12/25 06:00 [pubmed]
PHST- 2011/03/03 06:00 [medline]
PHST- 2013/12/11 00:00 [pmc-release]
AID - STROKEAHA.110.593798 [pii]
AID - 10.1161/STROKEAHA.110.593798 [doi]
PST - ppublish
SO  - Stroke. 2011 Feb;42(2):330-5. doi: 10.1161/STROKEAHA.110.593798. Epub 2010 Dec 
      23.