肾素-血管紧张素系统三个关键基因与2型糖尿病肾病发病关系的研究

Association study of three key genes of renin-angiotensin system in the patients of type 2 diabetes with nephropathy

目的 了解肾素 血管紧张素系统 (RAS)中三个关键基因血管紧张素Ⅰ转换酶 (ACE)、血管紧张素原 (AGT)及Ⅰ型血管紧张素受体 (AGTR1)基因中的 4个多态位点是否与中国人 2型糖尿病及其合并的糖尿病肾病 (DN)的发生有关联。方法 在 173例上海地区中国汉族人中用PCR基因扩增 ,内切酶消化或同位素标记放射自显影等方法进行基因分析 ,比较DN组及其亚组和对照组各组间的基因频率 ,并用logistic回归分析各基因多态位点和其他因素对DN发病风险的影响。 结果 DN组的ACE基因等位基因D和DD型频率增高 (P分别为 0 .0 2 2和 <0 .0 0 1)。按病程划分 ,<5年及≥ 5年亚组与DN(- )组比较亦可见等位基因频率差异 ,但进一步按DD型和非DD型分组 ,并经连续校正试验发现其阳性主要表现在病程 <5年与DN(- )组比较中。DN组的AGT M2 35T多态位点基因型和等位基因频率与未合并DN的糖尿病组比较有显著意义 (P分别为 0 .0 18和 0 .0 0 4) ,表现为等位基因T与TT型增多 ,且仅表现于病程 <5年亚组。不同病期DN亚组间的基因频率无显著变化。ACE、AGT及AGTR1基因四个多态位点与合并的高血压、冠心病等因素经logistic回归分析后提示ACE基因及AGT M 2 35T为DN ,尤其病程 <5年亚组的发病风险因素。结论 RAS中ACE基因I/D和AGT基因M 2 35T多?

Objective To clarify whether genetic variants of three key genes of the renin-angiotensin system (RAS) contribute to the development of diabetic nephropathy (DN) in Chinese. Methods (1) One hundred and seventy-three Chinese subjects of Han nationality from Shanghai were classified into control, DN(-) and DN(+) groups. The latter was subdivided according to diabetic duration at the onset of DN and the stage of DN. (2) Genotyping of four polymorphic sites in three key genes of the RAS: angio tensinogen (AGT)-T174M, AGT-M235T and angiotensinogen receptor 1 (AGTR 1) genotypes were determined by PCR/restriction enzyme digestion. The insertion/deletion (I/D) polymorphic marker was used for angiotensin converting enzyme (ACE) genotyping. (3) Statistical analysis: Comparisons of gene frequencies between any two groups were made with Fisher′s exact test or Chi-square test. Logistic regression analysis was performed to identify predictors of DN. Results The frequencies of ACE-DD genotype and ACE-D allele were much higher in DN(+) group than those in DN(-) group (0.25 vs 0.05 and 0.47 vs 0.29 respectively), sowerethefrequenciesofAGT-M235Tgenotype and AGT-235T allele (0.73 vs 0.54 and 0.85 vs 0.68 respectively). DN(+) duration<5 years group had greatly increaced frequency of AGT-235T allele and ACE-DD genotype in comparison with DN(-) group (0.92 vs 0.68 and 0.28 vs 0.05 respectively). Logistic regression analysis further identified these two genes as contributing factors to DN. Although AGTR1 and AGT-T174M genotyping analysis revealed differences in frequency distribution between DN(+) and DN(-) or control groups, logistic regression analysis failed to implicate them in the development of DN. Conclusion RAS genes, ACE I/D and AGT-M235T but not AGT-T174M and AGTR1-A1166Cpolymorphisms are contributing factors for DN in type 2 diabetes mellitus in Chinese.