Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction.
OBJECTIVE
Recent studies have implicated the potential importance of peroxisome proliferator-activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction.


RESULTS
Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024).


CONCLUSIONS
In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.
Ridker
Paul M
PM
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave East, Boston, Mass 02215, USA. pridker@partners.org
Cook
Nancy R
NR
Cheng
Suzanne
S
Erlich
Henry A
HA
Lindpaintner
Klaus
K
Plutzky
Jorge
J
Zee
Robert Y L
RY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D003062:Codon / Q000235:genetics; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D015994:Incidence; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics*; D012306:Risk; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D003062:Codon; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors