A Molecular Epidemiology Study On The Association Of PPARγ And RXRα Genes Polymorphisms And The Susceptibility Of Type 2 Diabetes

Diabetes is one of the top five kinds diseases in morbidity and mortality in the world. Type 2 diabetes mellitus (T2DM) which accounts for more than 95% of the number of diabetes developed into the issue of global importance quickly. Diabetes is an obvious heterogeneity with multiple environmental factors and multiple genetic diseases and its mode of inheritance and pathogenesis are very complex. It needs to research urgently. More than 95% of diabetes are characterized by insulin dysfunction and lack ofβcell insulin secretion in the world.Diabetes is metabolic disorders of glucose and lipid and insulin resistance is a central part of their diseases. And adipose tissue not only stores excess energy in the organization, while also regulating the metabolism of endocrine tissue and the secretion of adiponectin had been associated with T2DM closely. In addition to adiponectin gene polymorphisms, the level of adiponectin also are influenced by the relevant regulatory genes. In the promoter region of encoding ADIPOQ gene, it exists functional PPRE of PPARγreceptor. The synthesis of heterodimers between PPARγand RXRαtogether activate the transcription of adiponectin gene directly with PPRE. PPARγand RXRαare signaling pathway genes of adiponectin and they may play a role in insulin resistance or T2DM by its phenotype (plasma adiponectin). In this study, we conducted a case - control study design and used PCR-RFLP-based detection technology. We aimed to investigate the association of PPARγand RXRαgenes polymorphisms and the susceptibility of T2DM in southeast Han population of China. PartⅠSNPs in PPARγgene and type 2 diabetes riskPPARγis a ligand activated transcription factor. It's a member of the nuclear receptor family and expressed mainly in the liver and adipose tissue. Human PPARγgene located on chromosome 3p25 and involved in regulation of fat cell differentiation, lipid and carbohydrate metabolism and other processes. In the treatment of T2DM, PPARγis a target through the insulin sensitizer—thiazolidinediones (TZDs) which regulates the secretion of lipids, fatty acid metabolism and insulin sensitivity. PPARγligands are widely used in treatment of dyslipidemia and diabetes, thus PPARγis one of candidate genes to study the metabolic syndrome and T2DM. By utilizing a SNP haplotype approach, we tested, in a case-control study of a Chinese Han population, the hypothesis that common genetic variations in the PPARγgene may be associated with T2DM risk and may contribute to insulin-secretary defects and/or insulin resistance in T2DM. We tested 3 SNPs of PPARγgene in T2DM patients (n=541) and normal controls (n=607). Associations between genotypes and T2DM risk (ORs and 95%CI) were estimated by logistic regressions. The main results were as follows:1. The distribution in cases and controls of SNPs of PPARγWe analyzed three SNPs of PPARγ. After adjustment for age, sex, and BMI, the variants of rs3856806 (C>T) and rs17817276 (A>G) were negatively associated with risk of T2DM. The variants genotypes of rs3856806CT, rs3856806CT/TT and rs17817276GG were associated with lower T2DM risks[adjusted ORs(95%CI) = 0.71(0.54-0.92), 0.69(0.53-0.90), 0.40(0.17-0.94)], compared with the wild-type homozygote respectively. And the significances remained for rs3856806 and rs17817276 after the 1000 permutation test. No evidence suggested rs1801282 SNP was associated with T2DM.2. Stratified analysis of SNPs of PPARγIn stratified analysis, rs3856806CT genotypes might be protective factors in female,elderly group (age>50) and obese individuals[adjusted ORs(95%CI) = 0.60(0.42-0.87), 0.73(0.55-0.97), 0.47(0.24-0.90)], compared with the wild-type homozygote respectively. Rs17817276GG genotypes also might be protective factors in male,younger group(age≤50) and non-hypertensive individuals[adjusted ORs(95%CI) = 0.17(0.38-0.78), 0.07(0.01-0.67), 0.18(0.04-0.79)], compared with the wild-type homozygote respectively. Whereas, rs1801282 CC/CG/GG had no such effect to each stratified groups.3. Comparison of serum levels of adiponecin in SNPs genotypes of PPARγIn the diabetic group, we found that compared with rs3856806CC wild-type genotype, there was higher adiponectin level with homozygous rs3856806TT genotype in cases (P=0.015). Similarly we found that compared with rs17817276AA, AG wild-type genotype respectively, there was higher adiponectin level with homozygous rs17817276GG genotype in cases(P=0.03,0.019).4. Haplotype analysisHaplotype CAT, with variant allele T of rs3856806, was reduce the risk for T2DM compared with the most common haplotype CAC [ORs(95%CI) = 0.71(0.57-0.88)]. Also we found that Haplotype CGT, with variant allele T of rs3856806 and rs17817276G, was reduce the risk for T2DM compared with the most common haplotype CAC[ORs(95%CI) = 0.33(0.12-0.90)]. Whereas, other haplotypes were no such effect in groups.5. Crossover analysis in assessing gene-environmental interaction2*4 crossover analysis of rs3856806 and environmental risk factor (obesity) indicated that those who exposed to environmental risk factor had chances to develop T2DM[ORs(95%CI) = 1.52(1.11-2.09)], compared with those who did not expose the two factors. But those who simultaneously exposed to mutation genotypes and environmental risk factor had no significance to develop diabetes [ORs(95%CI) = 1.06(0.76-1.48)]. It shows the role of genetic and environmental risk was offset. Similarly, for the analysis of rs17817276, those who simultaneously exposed to mutation genotypes and environmental risk factor had a statistical significance to develop diabetes[ORs(95%CI) = 1.48(1.08-1.93)]. It showed that role of environmental risk was more than the protection of rs17817276AG/GG genotypes.PartⅡGene-gene interaction between PPARγand RXRαgene and type 2 diabetic riskIn the promoter region of encoding ADIPOQ gene, it exists functional PPRE of PPARγreceptor. The synthesis of heterodimers between PPARγand RXRαtogether activate the transcription of adiponectin gene directly with PPRE. PPARγand RXRαare signaling pathway genes of adiponectin and they may play a role in insulin resistance or T2DM. However, there's little reported between RXRαpolymorphisms and diabetes. To model the statistical interactions, we used the MDR method for the analysis of higher-dimensional non-linear interactions between gene-gene attributes.1. The distribution in cases and controls of SNPs of RXRαNo evidence suggested rs6537944 and rs1045570 SNPs were associated with T2DM after adjustment for age, sex, and BMI.2. Stratified analysis of SNPs of RXRαIn stratified analysis, rs6537944CC genotypes might be risk factors in younger group (age≤50) [adjusted ORs(95%CI) = 2.45(1.13-5.31), compared with the wild-type homozygote]. Whereas, rs1045570 CC/CT/TT had no such effect to each stratified groups.3. Haplotype analysisHaplotypes had no such effect in groups.4. Comparison of serum levels of adiponecin in SNPs genotypes of RXRαWe found no significance.5. Gene-gene interaction between PPARγand RXRαGenotypes data were analyzed in two genes of all SNPs in cases and controls by the MDR method. The results showed that X3 (rs17817276) model was statistically significant (P=0.001). The other three models were not statistically significant (P>0.05). Although the cross-validation consistency for the X3 model was 10/10, it only showed a single SNP role of PPARγgene rs17817276. We found no gene-gene interaction in T2DM.