| Type 2 diabetes mellitus（T2DM）is a common metabolic disease threatened to human health,with the incidence rising in the world.Genetic factors play an important role in its development.Identification of susceptible loci and construction of genetic risk score（GRS）for T2DM are useful for elucidating genetic mechanisms and providing early warnings of T2DM.The contents and main findings are as follow:firstly,we explored the association between PLA2G6 gene and T2DM in Han Chinese through a two-stage case-control study.In the first stage,15 tagging single nucleotide polymorphisms（SNPs）within PLA2G6 region were genotyped in 3,700 Chinese case-control individuals.We found that rs132984 and rs2284060 were significantly associated with T2DM（rs132984:OR=1.247,95%CI=1.074-1.449,P=0.004;rs2284060:OR=1.173,95%CI=1.059-1.299,P=0.002）.In the second stage,we genotyped rs132984 and rs2284060 in another case-control population（n=3,122）for replication.The results showed that rs132984 was significantly associated with T2DM（OR=1.280,95%CI=1.094-1.497,P=0.002）,while rs2284060 had no association with T2DM（P=0.297）.Meta-analysis showed that the two SNPs were both significantly associated with T2DM in Chinese(rs132984:OR=1.254,95%CI=1.104-1.451,P=4.85×10-5;rs2284060:OR=1.120,95%CI=1.046-1.195,P=0.003)after combining the data from the two stages.In addition,rs132984 was associated with area under curve of glucose in oral glucose tolerance test（OGTT）and triglyceride levels（P=0.030 and 0.044,respectively）.Our findings indicated that common variants of PLA2G6 had an association with T2DM and triglyceride levels in a Chinese Han population.Secondly,we constructed a GRS and evaluated its predictive effects on T2DM and progression of beta cell function in the Chinese population.We genotyped 89 SNPs reported to be associated with T2DM in the Chinese cross-sectional population（n=6,822）.From the results,we identified 40 SNPs that were significantly associated with diabetes risk（P<0.05）.Then we constructed a GRS based on the 40 SNPs and evaluated its predictive effects in a 9-year prospective cohort study（n=2,495）.We found that GRS could predict the incidence of T2DM and impaired glucose regulation（IGR）in logistic regression（OR=1.236,95%CI=1.100-1.389,P=0.0004）as well as in the Cox model（HR=1.129,95%CI=1.026-1.242,P=0.0128）after adjusting for age,sex,BMI,smoking and alcohol status at baseline.Moreover,GRS predicted deterioration in beta cell function（β=-0.0480,P=9.66×10-55 andβ=-0.0303,P=3.32×10-55 for Stumvoll first-and second-phase insulin secretion,respectively）.In addition,β-GRS also could predict combined T2DM and IGR in logistic regression（OR=0.809,95%CI=0.717-0.914,P=0.0006）and in the Cox model（HR=0.963,95%CI=0.928-0.998,P=0.0410）after adjusting for age,sex and BMI.Our findings indicated that GRS predicted blood glucose deterioration arising from change in beta cell function in the Chinese population.In conclusion,we identified a susceptible gene PLA2G6 and constructed a GRS prediction model of T2DM to screen for high risk populations. |
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