Ridker Paul M, Cook Nancy R, Cheng Suzanne, Erlich Henry A, Lindpaintner Klaus, Plutzky Jorge, Zee Robert Y L
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave East, Boston, Mass 02215, USA.
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):859-63. doi: 10.1161/01.ATV.0000068680.19521.34. Epub 2003 Mar 27.
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.
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).
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.
近期研究表明，过氧化物酶体增殖物激活受体作为动脉粥样硬化血栓形成相关分子机制具有潜在重要性。过氧化物酶体增殖物激活受体γ-2基因（PPARG2）第12密码子处常见的脯氨酸（P）被丙氨酸（A）取代，与2型糖尿病发病风险降低有关。鉴于糖尿病和动脉粥样硬化血栓形成有共同的发病基础，我们探究该多态性是否也与心肌梗死风险降低有关。
利用前瞻性队列研究中14916名初始健康的美国男性基线时采集的DNA样本，在平均随访13.2年期间，我们评估了PPARG2中P12A多态性，其中523人随后发生心肌梗死，2092人未报告有心血管疾病。正如所假设的，A12等位基因的存在与心肌梗死风险显著降低相关（年龄和吸烟调整后的显性遗传模型中，比值比为0.77；95%可信区间为0.60至0.98；P = 0.034）。在控制传统心血管危险因素的分析中，这种保护作用仍具有统计学意义，在非糖尿病研究参与者中也存在，在共显性或显性遗传模式分析中观察到其作用程度相似，在事后完全调整分析中也可见，我们将对照组限制为与心肌梗死病例特异性匹配的个体（比值比为0.71；95%可信区间为0.53至0.96；P = 0.024）。
在该队列中，PPARG2第12密码子处常见的P被A取代与心肌梗死发病率降低有关。如果在其他队列中得到证实，这些数据将对心血管疾病的新治疗方法有启示，包括开发针对PPARG的疗法。
