Association Of ENPP1 Polymorphisms With Type 2 Diabetes Mellitus

Objective: Type 2 diabetes mellitus(T2DM)is a complex metabolic disease characterized by insufficient insulin secretion,which may be attributed to impaired insulin sensitivity and increased insulin resistance.Numerous studies reveal that polymorphisms in ENPP1 are associated with T2 DM.This study was conducted to investigate whether polymorphisms in ENPP1 are involved in the pathogenesis of T2 DM,and to explore the potential risk polymorphisms for early screening,prevention and delay of the onset of T2 DM.Methods: A community-based,1:1 case-control study was conducted in Nanning City,with a total of 1586 subjects(793 patients and 793 controls).MALDI-TOF-MS was used to genotype three polymorphisms in ENPP1(rs7754586,rs2327154 and rs55725924)to explore the potential risk genotypes and alleles.Mc Nemar or Bowker test was used to compare the proportional differences between categorical variables.Student's dependent t-test was conducted to examine the differences between the numerical data.PLINK was used to examine the association between the three polymorphisms in ENPP1 and the risk for T2 DM and the differences in the distribution of three polymorphisms between cases and controls,and MDR software was ultilized to test the interaction of genetic variants with environmental factors.SHEsis platform was used to construct the haplotypes,and general linear model analysis was ultilized to compare the differences in the quantitative traits among subjects with different genotypes.Results:(1)In the general population,there was no significant association between these polymorphisms and T2 DM risk.The patients with the genotype AA of rs7754586 had a lower TG level(P = 0.045),but a higher HDL level(P = 0.008)compared with those with the genotype CC of rs7754586,and these associations remained signicant in dominant model(P = 0.023)and recessive model(P = 0.027).The patients with the genotype CC of rs55725924 had higher FBG(P = 0.018)and Hb A1 c levels(P = 0.008)compared with those with the genotype TT or combined TT and TC,and the 2h BG level in patients with the genotype CC was higher than that in those with combined TT and TC(P = 0.042).The patients with the genotypes TT and CT of rs2327154 had a lower LDL level(P = 0.048)compared with those with the genotype CC,and the patients with TT had a lower DBP level than those with CC(P = 0.013).However,in the control group,only the difference in DBP level was significant between subjects with the genotype AA of rs7754586 and with combined CC and CA(P = 0.009).Rs55725924 and rs2327154 were not associated with all metabolic traits(P > 0.05).(2)In the male population,the distribution of allele of rs7754586 in patients and controls was statistically different(50.67% vs 45.81%,P = 0.046).The subjects carring the genotype AA showed a higher risk of acquiring T2 DM,and after adjustment of age,smoking,drinking,activity and BMI,the association remained(OR = 1.275,95%CI:1.007-1.641).The patients with the genotype AA of rs7754586 had a lower TG level(P = 0.002),but a higher HDL(P = 0.042)and LDL(P = 0.030)levels than those carring the genotype CC.The patients with AA and CA had lower TG(P = 0.023)and LDL(P = 0.039)levels than those with CC.The patients with AA had a lower TG level(P = 0.016),but a higher HDL level(P = 0.014).The patients with the genotype CC of rs55725924 had a higher BMI level than those with TT(P = 0.016)or with combined TT and TC(P = 0.015).In the control group,all polymorphisms were not associated with these metabolic traits(P > 0.05).(3)In the female population,there was no significant association between these polymorphisms and T2 DM risk.The patients with the genotypes CA and AA of rs7754586 had a higher HDL level(P = 0.043)than those with CC.The patients with the genotype CC of rs55725924 had a higher Hb A1c% level than those with TT(P = 0.021)or combined TT and TC(P = 0.023).The patients with the genotype TT of rs2327154 had a lower SBP level with those with CC(P = 0.003)or combined CC and CT(P = 0.016).However,in the control group,these polymorphisms were not associated with all metabolic traits(P > 0.05).(4)The differences in the distribution of haplotypes consisting of three polymorphisms in ENPP1 were not statistically significant between the case group and the control group in the total,female and male populations(P >0.05).(5)Mutifactorial dimension reduction analysis suggested the interaction between rs7754586,rs2327154 and environmental factors(BMI,physical activity and TG level).Conclusions:(1)In the total population,the allele A of rs7754586 may be related to lower TG and SBP levels,but a higher HDL levels,and the allele C of rs55725924 may be related to higher FBG,2h BG and Hb A1 C levels,and the allele T of rs2327154 may be associated with a lower DBP and LDL levels.(2)In the male population,the genotype AA and allele A of rs7754586 may contribute to the incidence of T2 DM,and were associated with lower TG level,but higher HDL and LDL levels.The allele C of rs55725924 may be associated with a higher BMI level.(3)In the female population,the allele A of rs7754586 may be related to a higher HDL level,and the allele C of rs55725924 may be associated with a higher Hb A1 C level,and the allele T of rs2327154 may be related to lower SBP and DBP levels.(4)The haplotypes constructed from these three polymorphisms may be not associated with the risk of T2 DM,and rs7754586 and rs2327154 may interact with BMI,physical activity,and TG.