Association Of Adiponectin Gene Single Nucleotide Polymorphisms With Type 2 Diabetes Mellitus In Han Population

Objective: 1. To investigate the distribution of adiponectin gene (APM1) IVS2 +712A/G, IVS2+349A/G and Exon 3 +331T/C polymorphisms in Han population in Sichuan province of China and its association with type 2 diabetes mellitus (T2DM).2. To explore the impact of these APM1 polymorphisms on phenotypes in T2DM patients, including blood glucose, lipid metabolism and insulin sensitivity.Methods: In this population-based, case-control genetic association study, a total of 819 subjects was recruited from the community, including 405 T2DM patients and 414 unrelated healthy control individuals. Fasting blood glucose (FPG), Fasting insulin (FINS) and Serum lipid levels were detected. The body mass indexes (BMI) and the waist-to-hip ratios (WHR) were calculated. The homeostasis model assessment (HOMA) was used to measure insulin resistance (IR). Three SNPs, APM1 gene IVS2 +712A/G, IVS2 +349A/G, Exon3 +331T/C were identified by means of PCR-RFLP. Data were analyzed with SPSS13.0 software. Linkage disequilibrium and haplotype frequencies were analyzed by SHEsis software online.Results: 1. The frequencies of APM1 gene IVS2+712 AA/AG/GG/(AA+AG) genotype in T2DM group and control group were respectively as bellows: 123/117 (29.7%/28.9%),195/218(47.1%/53.8%),96/70(23.2%/17.3%),318/335(76.8%/82.7%).The frequencies of APM1gene IVS2+712 A/G allele in T2DM group and control group were respectively as bellows: 441/452(53.3%/55.8%), 387/358(46.7%/44.2%). The distribution frequencies of the alleles and genotypes were in agreement with the Hardy Weinberg equilibrium (P>0.05). No significant difference was found in allele frequencies and genotype distributions of APM1 gene IVS2 +712A/G polymorphism between patients with T2DM and control subjects (P>0.05). However, with AA and AG genotypes combined,compared with GG genotypes, significant differences could be found between patients with T2DM and control subjects (χ~2=4.416,P=0.036,OR =1.445,95%CI=1.024~2.038). Further study on serum lipid levels in T2DM group indicated that levels of TC and LDL-C had significant differences between patients with GG genotype and AA+AG genotype. Patients with GG genotypes had higher levels of TC and LDL-C (F1=8.400,P1=0.004;F2=8.486,P2=0.004).No significant difference was found in other phenotypes with different genotypes in each group (P>0.05).2. The frequencies of APM1 gene IVS2+349 AA/AG/GG genotype in T2DM group and control group were respectively as bellows: 227/216(54.8%/53.3%), 159/165(38.4%/40.7%), 28/24(6.8%/5.9%).The frequencies of APM1 gene IVS2 +349A/G allele in T2DM group and control group were respectively as bellows: 613/597(74.0%/73.7%), 215/213(27.0%/26.3%). The distribution frequencies of the alleles and genotypes were in agreement with the Hardy Weinberg equilibrium (P>0.05). No significant difference was found in allele frequencies and genotype distributions of APM1 gene IVS2 +349A/G polymorphism between patients with T2DM and control subjects (P>0.05). Further study on serum lipid levels and insulin sensitivity indicated that there were no significant difference with different genotypes in each group (P>0.05).3. All the genotypes of APM1 gene Exon 3 +331 site detected were TT homozygote.4. APM1 gene IVS2 +712A/G and IVS2 +349A/G polymorphisms displayed strong linkage disequilibrium (D'=0.893, r2 =0.235). No significant difference of haplotype frequencies was found between T2DM group and control group.5. Logistic regression model was used to evaluate the odds ratios of risk for T2DM associated with APM1 gene polymorphism. The result showed that the factors which finally entered the regression equation were sex, HDL-C, LDL-C and IVS2 +712 site GG genotype.Compared with AA genotype, there was a significant relationship between GG genotype of APM1 gene IVS2 +712 site and T2DM after adjusting for BMI, age and sex (P=0.030, OR=1.623, 95%CI=1.047~2.516). Moreover, the relationship also had interaction with sex and serum lipids to some extent.6. Comparison of distributions of APM1 gene genotypes and alleles among different ethnic populations:(1)for IVS2 +712 site,the major allele of Chinese,Japanese and African is A,while it's G of Caucasian.(2) for IVS2 +349 site,the frequency of A allele in Chinese is similar with Japanese,while it's lower than European and African.(3)for Exon3 +331 site,no polymorphism was found in the Han population in Sichuan province of China,while it's detected as an polymorphism site in other ethnic populations.Conclusion: 1.The GG genotype of APM1 gene IVS2 +712 site may be associated with the occurrence of T2DM and increase the genetic risk of developing T2DM together with lipids disorder. APM1 gene IVS2 +349A/G polymorphisms is not associated with T2DM but tightly linked with IVS2 +712A/G.2. The polymorphism in APM1 gene Exon 3 +331 site is not found in Han population in Sichuan in our study.3. The polymorphisms in APM1 gene exhibit ethnic difference.