Association Between Polymorphisms Of TCF7L2 And Type 2 Diabetes Mellitus In Uygur Population Of Xinjiang Region

Objective: The aim of the present study was to investigate the association of transcription factor 7-like 2(TCF7L2) gene polymorphisms with T2 DM in a Uygur population of Xinjiang. Methods: In this case-control study,1000 cases of T2 DM patients were recruited in T2 DM group and 1007 healthy examination individuals were selected as control. Clinical data and blood sample was collected from each subject, genomic DNA was extracted from whole peripheral blood leukocytes. The TCF7L2 gene polymorphism was detected by matrix-assisted laser desorption/ionization–time of flight(MALDI-TOF).Analyze the relationship between susceptibility to T2 DM and different genotypes. All statistical analysis was performed by using SPSS 17.0 software. Results: ① The frequencies of GG, GT and TT genotype on TCF7L2 rs12255372 in T2 DM group were64.9%, 31.0% and 4.1%, respectively; whereas those in control group were 70.1%, 27.0%and 2.9% respectively. Significant differences in the frequencies of TCF7L2 rs12255372 genotype were found between T2 DM and control group(x2=6.592, P=0.037). The frequencies of G and T allele on TCF7L2 rs12255372 in T2 DM group were 80.4% and19.6%, respectively; whereas those in control group were 83.6% and 16.4% respectively.Significant differences in the frequencies of TCF7L2 rs12255372 allele were found between T2 DM and control group(x2=6.706, P=0.010). As compared with G allele,patients with T allele had a significantly higher risk of the type 2 diabetes mellitus with OR of 1.242(95%CI: 1.054~1.464). The frequencies of TT, TC and CC genotype on TCF7L2 rs7901695 in T2 DM group were 61.5%, 32.9% and 5.6%, respectively; whereas those in control group were 67.5%, 29.1% and 3.4% respectively. Significant differences in the frequencies of TCF7L2 rs7901695 genotype were found between T2 DM and control group(x2=9.863, P=0.007). The frequencies of T and C allele on TCF7L2 rs7901695 in T2 DM group were 78.0% and 22.0%, respectively; whereas those in control group were82.0% and 18.0% respectively. Significant differences in the frequencies of TCF7L2rs7901695 allele were found between T2 DM and control group(x2=9.886, P=0.002). As compared with T allele, patients with C allele had a significantly higher risk of the type 2diabetes mellitus with OR of 1.290(95%CI: 1.100~1.512). ②A significant association between rs12255372 and T2 DM risk could also be found in additive genetic model(GT vs GG, P=0.033, OR=1.240, 95%CI=1.017~1.511) and dominant genetic model(GG vs GT+ TT, P=0.015, OR=1.267, 95%CI=1.048~1.533). A significant association between rs7901695 and T2 DM risk could also be found in additive genetic model(TC vs TT,P=0.032, OR=1.240, 95%CI=1.019~1.508; CC vs TT, P=0.011, OR=1.793,95%CI=1.145~2.809), in dominant genetic model(TT vs TC + CC, P=0.006, OR=1.298,95%CI=1.076~1.566), and in recessive genetic model(CC vs TT + TC, P=0.022,OR=1.672, 95%CI=1.073~2.608). ③The serum concentration of LDL, BUN were higher in T2 DM group with GT + TT genotype of rs12255372 than those with GG genotype,which showed a significant difference(P<0.05). The SBP, DBP were higher in control group with GT + TT genotype of rs12255372 than those with GG genotype, which showed a significant difference(P<0.05). The serum concentration of TG were lower in T2 DM group with TC + CC genotype of rs7901695 than those with TT genotype as well as the serum concentration of BUN were higher in T2 DM group with TC + CC genotype rs7901695 than those with TT genotype, which showed a significant difference(P<0.05).④ The two SNPs rs12255372 and rs7901695 were found to be in strong linkage disequilibrium with each other(T2DM group: D’=0.743, r2=0.137; control group:D’=0.849, r2=0.652) and therefore formed a haplotype block. The frequency of TT haplotype was significantly higher in subjects with T2 DM than in controls(P<0.001),whereas the frequency of GC, TC haplotype was significantly higher in controls than in subjects with T2DM(P<0.001).The two SNPs rs10885395 and rs7094463 were found to be in strong linkage disequilibrium with each other(T2DM group: D’=0.976, r2=0.157;control group: D’=0.923, r2=0.170) and therefore formed a haplotype block. The frequency of haplotype was no significantly different between in subjects with T2 DM and in controls(P>0.05). ⑤ The interaction between rs12255372 and drinking show that non-drinking and carrying GT+TT genotype was associated with a 1.339-fold increased risk for T2 DM when compared to non-drinking and carrying GG genotype, drinking and carrying GT+TT genotype were associated with a 0.499-fold increased risk for T2 DM when compared to non-drinking and carrying GG genotype, the result of interaction based on multiplicative model was statistically significant(P=0.028, OR=0.495, 95%CI=0.264~0.928). The interaction between rs7085532 and drinking show that drinking and carrying AA genotypewere associated with a 0.354-fold increased risk for T2 DM when compared to non-drinking and carrying AA genotype, drinking and carrying AG+GG genotype were associated with a 0.690-fold increased risk for T2 DM when compared to non-drinking and carrying AA genotype, the result of interaction based on multiplicative model was statistically significant(P=0.007, OR=2.314, 95%CI=1.253~4.273). The interaction between rs7901695 and low high-density lipoprotein hyperlipidemia appeared the best MDR model with statistical significance(P<0.0001). Testing balance accuracy was 0.6837 and cross-validation consistency was 10/10. Conclusion: ① The polymorphisms of rs12255372 in TCF7L2 gene may be associated with T2 DM in Uygur population from Xinjiang region, the T allele of rs12255372 was a risk factor for T2DM; The polymorphisms of rs7901695 in TCF7L2 gene may be associated with T2 DM in Uygur population from Xinjiang region, the C allele of rs7901695 was a risk factor for T2 DM.②The rs12255372 polymorphism of TCF7L2 gene has influence on level of serum LDL,BUN, SBP and DBP; The rs7901695 polymorphism of TCF7L2 gene has influence on level of serum TG and BUN. ③The two SNPs rs12255372 and rs7901695 of TCF7L2 were found to be in strong linkage disequilibrium with each other; The TT haplotype may be a risk factor of T2DM; The GC and TC haplotype may be a protective factor of T2 DM.④There were significant interactions between two SNPs rs12255372 and rs7085532 of TCF7L2 and drinking, there were significant interactions between rs7901695 of TCF7L2 and low high-density lipoprotein hyperlipidemia.