Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
Gene. 2013 Apr 25;519(1):50-4. doi: 10.1016/j.gene.2013.01.053. Epub 2013 Feb 8.
Reactive oxygen species are considered to play a role in the development of type 2 diabetes mellitus (T2DM) and its complications. 8-Oxoguanine, which is one of the major oxidation base lesions produced by reactive oxygen species, may cause G:C to T:A transversion mutations because it can mispair with adenine. hMTH1 (human mutT homolog 1), hOGG1 (human 8-oxoguanine glycosylase 1) and MUTYH (human mutY homolog) genes constitute the 8-oxoG repair pathway. In this study, we screened for the polymorphism variants Val83Met (c.247G>A, rs4866) in hMTH1; c.-53G>C (rs56387615), c.-23A>G (rs1801129) and c.-18G>T (rs1801126) in the 5'-UTR of hOGG1; and AluYb8 insertion in MUTYH (AluYb8MUTYH, rs10527342) and investigated their synergistic effect on the risk of T2DM in the Chinese population. The genotypes were determined by electrophoresis, a high-resolution melting technique and sequencing of PCR products. Our results showed that the c.247G>A variant in the hMTH1 gene increased the risk of T2DM in >55 years of age groups (OR=1.579; 95%CI: 1.029-2.421). The set of c.-53G>C, c.-23A>G and c.-18G>T variants detected in the 5'-UTR of the hOGG1 gene and the AluYb8 insertion in the MUTYH gene were each associated with an increased risk of T2DM (OR=1.507, 95%CI: 1.122-2.024; OR=1.229, 95%CI: 1.030-1.466, respectively). Combined analysis of the variations among the three genes suggested that the c.247G>A variant in hMTH1 combined with AluYb8MUTYH variant had a synergistic effect on increasing the risk of T2DM (OR=1.635; 95%CI: 1.147-2.330). This synergy was also observed between the variants in the 5'-UTR of the hOGG1 and the AluYb8MUTYH variant (OR=1.804; 95%CI: 1.254-2.595). Our results suggest, for the first time, the combined effects of AluYb8MUTYH with either hMTH1 c.247G>A or variants in the 5'-UTR of the hOGG1 on the risk of T2DM.
活性氧被认为在 2 型糖尿病（T2DM）及其并发症的发展中起作用。8-氧鸟嘌呤是由活性氧产生的主要氧化碱基损伤之一，可能导致 G:C 到 T:A 颠换突变，因为它可以与腺嘌呤错配。hMTH1（人 mutT 同源物 1）、hOGG1（人 8-氧鸟嘌呤糖苷酶 1）和 MUTYH（人 mutY 同源物）基因构成 8-氧鸟嘌呤修复途径。在这项研究中，我们筛选了 hMTH1 中的 Val83Met（c.247G>A，rs4866）；hOGG1 5'-UTR 中的 c.-53G>C（rs56387615）、c.-23A>G（rs1801129）和 c.-18G>T（rs1801126）；以及 MUTYH 中的 AluYb8 插入（AluYb8MUTYH，rs10527342），并研究了它们在中国人群中对 T2DM 风险的协同作用。基因型通过电泳、高分辨率熔解技术和 PCR 产物测序确定。我们的结果表明，hMTH1 基因中的 c.247G>A 变体增加了 >55 岁年龄组 T2DM 的风险（OR=1.579；95%CI：1.029-2.421）。在 hOGG1 基因 5'-UTR 中检测到的 c.-53G>C、c.-23A>G 和 c.-18G>T 变体以及 MUTYH 基因中的 AluYb8 插入与 T2DM 风险增加相关（OR=1.507，95%CI：1.122-2.024；OR=1.229，95%CI：1.030-1.466）。对三个基因中变异的联合分析表明，hMTH1 中的 c.247G>A 变体与 AluYb8MUTYH 变体结合具有协同作用，增加了 T2DM 的风险（OR=1.635；95%CI：1.147-2.330）。在 hOGG1 基因的 5'-UTR 中的变体与 AluYb8MUTYH 变体之间也观察到这种协同作用（OR=1.804；95%CI：1.254-2.595）。我们的结果首次表明，AluYb8MUTYH 与 hMTH1 c.247G>A 或 hOGG1 5'-UTR 中的变体的联合作用会增加 T2DM 的风险。
