| Type 2 diabetes is rapidly emerging as one of the greatest global health challenges of the 21st century. The World Health Organization estimates that by the year 2030,366 million people will be afflicted with diabetes. Developing better treatments and novel prevention strategies for type 2 diabetes is therefore a matter of great urgency.There are evidences that hyperglycemia results in the generation of reactive oxygen species (ROS), leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from the endogenous antioxidant network, the system becomes overwhelmed for redox imbalance leading to the activation of stress-sensitive pathways. One consequence is the production of gene products that cause cellular damage and are responsible for the late complications of diabetes ultimately.In most instances, the exact cause of type 2 diabetes seems to be polygenic in nature and is as yet unknown. Chronic hyperglycemia, the adverse outcome of the initial polygenic disorder, in time becomes an adverse force on theβcell, leading to a vicious cycle of continuous deterioration ofβcell function.Deeply understanding the inherited factors that influenceβcell function may lead to the development of better prevention and treatments strategies for T2DM. Among the panel of potential candidate genes, we found that HO-1, Nrf2, NOS3 and FTO genes were associated with oxidative stress-induced diseases, and oxidative stress could lead toβcell dysfunction. SLC30A8 gene was involved in the synthesis and secretion of insulin. Therefore, this study is to analyze the associations between susceptibility to T2DM and HO-1, Nrf2, NOS3 and FTO genes polymorphism, and to provide theoretical guidance in prevention and treatments strategies for T2DM. Part I Variants in Nrf2, NOS3 and HO-1 genes are associated with type 2 diabetes in a Chinese populationObjective:Our aim was to define the association of HO-1, Nrf2 and NOS3 polymorphism with newly diagnosed type 2 diabetes in a Chinese Han population. Moreover, we also define the association of HO-1, Nrf2 and NOS3 polymorphism with oxidative stress and anti-oxidative status.Methods:This polymorphism was genotyped in 2517 participants with newly diagnosed type 2 diabetes (n=884), impaired glucose regulation (n=306) and normal glucose tolerance (n=1327) using an allelic discrimination assay-by-design TaqMan method on ABI7900HT. We analyzed associations of the HO-1, Nrf2 and NOS3 polymorphism with susceptibility of T2DM through Logistic regression analysis. Furthermore, the possible association was analyzed between the risk allele and IR, HOMA-(3 cell, oxidative stress and anti-oxidative status.Results:To Nrf2 rs6721961 SNP, The ORs for homozygous genotypes AA vs. CC were 1.562 for T2DM (95%CI 1.110-2.200; P=0.011) and 1.480 for combined T2DM and IGR (95%CI 1.071-2.044; P=0.017). Carries of genotype AA showed a higher TAOC, SOD, CAT, GSH and GSH-Px and lower IR and MDA when compared with Carries of genotype CC or CA. In NOS3 rs 1799983 SNP, compared with Carries of genotype GG, Carries of allele T was significantly associated with risks of T2DM and combined T2DM and IGR (OR=0.766,95%CI 0.607-0.966, P=0.025; OR=0.796,95%CI 0.644-0.984, P =0.035, respectively). Carries of genotype TT showed a higher HOMA-(3 cell, SOD, CAT and GSH-Px and lower MDA when compared with Carries of genotype GG.Conclusions:Nrf2 rs6721961 SNP and NOS3 rs1799983 SNP are significantly associated with newly diagnosed T2DM in our population. Nrf2 rs6721961 SNP can increase the risk of T2DM, and NOS3 rs 1799983 SNP may low the risk of T2DM. The association is achieved by influencing oxidative stress and anti-oxidative status. PartⅡA genetic variation in FTO gene is associated with obesity and newly diagnosed type 2 diabetes in a Chinese populationObjective:We aimed to examine the associations of rs9939609 SNP with obesity and newly diagnosed type 2 diabetes (T2D) in a Chinese population.Methods:We genotyped rs9939609 in 2587 subjects (obesity 243, overweight 976, normal weight 1368 or newly diagnosed T2D 877, impaired glucose regulation 305, normal glucose tolerance [NGT] 1405) using an allelic discrimination assay-by-design TaqMan method on ABI7900HT. We analyzed associations of the rs9939609 SNP with obesity and newly diagnosed T2D through Logistic regression analysis. According to the Chinese criteria, we defined obesity as BMI>28 Kg/m2, overweight as 24 Kg/m2< BMI<28 Kg/m2 and normal weight as BMI<24 Kg/m2.2587 subjects gave informed consent and did not take any medication known to affect glucose tolerance before participation.Results:BMI for T2D vs. NGT is significant difference (P<0.001). Minor allele frequency of rs9939609 SNP was 0.133. Minor allele frequencies for obesity, overweight and normal weight were 0.158,0.151 and 0.115. In addition, Minor allele frequency for T2D, IGR and NGT were 0.151,0.144 and 0.120. In obesity case-control study, the odds ratios were 1.447 for Obesity vs. normal weight (95%CI 1.104-1.896; P=0.007) and 1.363 for Overweight vs. normal weight (95%CI 1.149-1.617; P<0.0001). In T2D case-control study, the odds ratios were 1.305 for T2D vs. NGT (95%CI 1.097-1.552; P=0.003) and 1.280 for combined T2D and IGR vs. NGT (95%CI 1.089-1.503; P=0.003). After adjustment for age, sex and BMI, the ORs were 1.270 and 1.241 for T2D vs. NGT and combined T2D and IGR vs. NGT (95%CI 1.048-1.540; P=0.015 and 95%CI 1.035-1.489; P=0.020). Our results showed obesity subjects had strongly increased risks of IGR and T2D (P<0.0001 and P<0.0001). The ORs for obesity vs. normal weight were 4.351 for IGR (95%CI 2.293-8.258; P<0.0001),3.578 for T2DM (95%CI 2.385-5.368; P 0.0001) in carriers of genotype TT and 6.758 for IGR (95%CI 2.456-18.597; P=0.0002),4.898 for T2D (95%CI 2.409-9.960; P<0.0001) in carriers of genotype AA/AT. Similarly, compared with normal weight subjects, overweight subjects had strongly increased risks of IGR and T2D in carriers of genotype TT or genotype AA/AT (P<0.0001, P<0.0001, P<0.0001 and P=0.0004, respectively)Conclusion:The FTO gene rs9939609 SNP is strongly associated with risk of obesity and newly diagnosed T2D in the Chinese population.PartⅢThe SLC30A8 polymorphism is associated with type 2 diabetes and impaired glucose Regulation in a Chinese Han populationObjective:Our aim was to define the association between this polymorphism and newly diagnosed type 2 diabetes and impaired glucose regulation in a Chinese Han population. The meta-analysis was undertaken to integrate previous findings and summarize the effect size of SLC30A8 rs13266634 polymorphism associated with susceptibility of T2DM. We also explore whether the SNP is associated with pancreatic beta cell function in our study population.Methods:This polymorphism was genotyped in 2918 participants with newly diagnosed type 2 diabetes (n=1036), impaired glucose regulation (n=343) and normal glucose tolerance (n=1539) using an allelic discrimination assay-by-design TaqMan method on ABI7900HT. We analyzed associations of the rs13266624 SNP with susceptibility of T2DM through Logistic regression analysis. Analyses were conducted in RevMan 5.0 software packages developed by the Cochrane Collaboration and were used for visualizing the overall effect and evaluating publication bias. Furthermore, the possible association was analyzed between the risk allele and insulin resistance and the pancreatic beta cell function.Results:Compared to the allele T, the allele C was significantly associated with increased risks of T2DM and combined T2DM and IGR (OR=1.199,95%CI 1.059-1.358, P=0.004; OR=1.214,95%CI 1.081-1.364, P=0.001, respectively). The ORs for homozygous genotypes CC vs. TT were 1.365 for T2DM (95%CI 1.081-1.723; P=0.009) and 1.398 for combined T2DM and IGR (95%CI 1.124-1.740; P=0.003). Moreover, the OR for homozygous genotypes CC vs. TT and the OR for allele C vs. T were higher for IGR compared with T2DM and combined T2DM and IGR (OR=1.506,95%CI 1.078-2.103, P=0.016; OR=1.259,95%CI 1.056-1.500, P=0.010, respectively). After Meta analysis for the studies about the association of rsl3266634 SNP with susceptibility of T2DM, the total OR is 1.15 (95%CI 1.10-1.20). There was a significantly decreased HOMA-beta in participants carrying genotype CC compared with those with genotype TT (P=0.003).Conclusions:The risk allele C of the SLC30A8 rsl3266634 polymorphism is significantly associated with newly diagnosed T2DM and IGR in our population. The association is achieved by influencing the pancreatic beta cell function. |
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