Alanine for Proline Substitution in the Peroxisome Proliferator–Activated Receptor Gamma-2 (PPARG2) Gene and the Risk of Incident Myocardial Infarction

Abstract

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. Methods and 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; Pϭ0.034). 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; Pϭ0.024). Key Words: genetics Ⅲ epidemiology Ⅲ myocardial infarction Ⅲ risk prediction Ⅲ polymorphism R ecent data suggest that a common alanine for proline substitution at codon 12 (P12A) in the peroxisome proliferator-activated receptor gamma-2 gene (PPARG2) is associated with reduced incidence of type 2 diabetes. [1][2][3][4] This observation is of considerable interest because patients with diabetes have accelerated atherosclerosis and insulin resistance is now recognized as a risk factor for myocardial infarction (MI). Recent experimental work has implicated that PPARG may act directly on local vasculature in several critical aspects of atherothrombosis, including lipid metabolism, foam cell responses, and inflammation, additionally suggesting that PPARG may be an important determinant of gene expression during atherogenesis. 5,6 We therefore hypothesized that the P12A polymorphism in the PPARG2 might also be a determinant of incident myocardial infarction (MI). Conclusions-In Methods Patient Selection and Clinical InvestigationWe sought evidence of association between a common P12A polymorphism in the PPARG2 and risk of incident MI as part of an ongoing genetic epidemiology evaluation of incident cardiovascular events being performed within the Physicians' Health Study. 7 In brief, of 22 071 American men aged 40 to 84 years who were free of prior MI, stroke, transient ischemic attack, and cancer, 14 916 provide...

Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes

“…This is consistent with the emerging view that variation at the PPARG locus is likely to have pleiotropic effects, modulating susceptibility to hypertension and myocardial infarction [8,9,10]. The Ala12 variant could therefore provide protection not only from developing Type 2 diabetes, but also from more general metabolic morbidity.…”

Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus

“…We have exploited advanced record-linkage technology developed through DARTS to enable all individuals in the cohort to be prospectively followed with a high degree of sensitivity and specificity 22 and have confirmed a previous report that the Ala allele of Pro12Ala is associated with a reduced hazard of myocardial infarction. 13 Furthermore, we have demonstrated that the T allele of C1431T is associated with an increased hazard and that its coexistence influences the hazard associated with the Ala allele. The potential importance of the T1431 variant as a marker for cardiovascular risk is supported by a recent case control study from Taiwan that considered this variant in isolation and demonstrated a significantly increased risk of premature myocardial infarction as well as an increased level of atherogenic oxidized low-density lipoprotein-cholesterol associated with T1431 homozygotes.…”

“…[7][8][9] Notably, the Ala allele of the Pro12Ala polymorphism has been associated with greater insulin sensitivity, 7,9 reduced risk of type 2 diabetes, 10 reduced body mass index (BMI), 11 lower blood pressure, 12 and reduced risk of myocardial infarction. 13 Furthermore, the action of this variant may be subject to interaction with diet and exercise. 14,15 We demonstrated previously that a further silent variant in exon 6 of PPARG, C1431T, which is in strong linkage disequilibrium (LD) with the Pro12Ala variant, has an opposing association with body mass in several populations with and without type 2 diabetes.…”

Association between Pro12Ala polymorphism of peroxisome proliferator‐activated receptor‐gamma 2 and myocardial infarction in the Chinese Han population

“…The frequency of the Ala allele in the control group was consistent with that of the Han population in Beijing and Guangdong in China and that of Japanese, 4 whereas the frequency of the Ala allele was significantly lower than that in Uygur population (10.4%) of Xinjiang in China and that in Americans. 6 These data indicate that there is an ethnic difference in Pro12Ala genotype and allele frequency distribution.…”

“…In contrast to our study, other research shows that Pro12Ala polymorphism is associated with a reduced risk of the incidence of MI in initially healthy men. 6 The former study was carried out by a nested case-control design in a prospective cohort investigation among 121,700 female and 51,529 U.S. male health professionals, with a follow-up of 8 and 6 years, respectively. Furthermore, the latter was carried out by a nested case-control design in a prospective cohort of 14,916 initially healthy American men, with a follow-up of 13.2 years.…”