Association Of Hnf1a, Gck And Gckr Gene Polymorphism With Gestational Diabetes Mellitus In A Chinese Population

Background and ObjectivesGestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. It affects 5% to 10% of Asian women and this frequency is continuously increasing in some developing countries, including China. Epidemiological study has confirmed that GDM is associated with increased feto-maternal morbidity and long-term complications in mothers and offspring. However, the specific pathogenesis of GDM is still unknown. Some studies identify that genetics may play an important role on the GDM. Until recently, however, no one has reported a genome-wide association (GWA) study or a large-scale genetic linkage analysis of GDM. Thus, some researchers have attempted to study whether the candidate genes of type 2 diabetes. Both GDM and MODY have the same features as early onset andβcell dysfunction. The gene polymorphisms of MODY might increase the prevalence of GDM. So far, only a few studies with large samples have investigated the relationship between the gene polymorphisms of MODY and gestational diabetes, but their results were not coincident.Our aim of this study was to investigate the correlation between HNF1 A, GCK, GCKR gene polymorphism (HNF1A rs1169288,GCK rs1799884,GCKR rs780094) and GDM in a Chinese population. The single nucleotide polymorphism(SNP) of GCKR is firstly investigated in GDM population.Methods1. SubjectsAll pregnant women were screened for GDM between 24 and 28 weeks with a 50g glucose challenge test (GCT). Plasma glucose 1 hour after intake of glucose less than 7.8 mmol/1 was defined as GCT negative (GCT-), otherwise, diagnosed as GCT positive (GCT+). GCT+ women were then administered a 100 g oral glucose tolerance test. Based on ADA criteria,2088 pregnant women were included in the study; 668 with GDM,376 with GIGT,758 with NGT and 286 who were GCT-2. Collection of subjects'clinical and biochemical data.3. Genetic analysis:Genomic DNA was obtained from human leukocyte nuclei isolated from whole blood. HNF1A rs1169288, GCK rs1799884, GCKR rs780094 gene polymorphisms were genotyped by the TaqMan allelic discrimination assay. The genotyping results were verified by direct sequencing.Results1.Comparison of clinical and biochemical parameters in subjects1)The differences of age, gravidity, parity, systolic blood pressure(SBP),diastolic blood pressure(DBP),white blood cell(WBC) counting, platelet(PLT) counting, real insulin during OGTT, glycosylated hemoglobin (HbAlc), triglyceride(TG), hypersensitivity C reaction protein(hsCRP), body weight(BW) increment during pregnancy, the positive ratio of diabetes family history, the percentage of bad pregnancy and delivery history and the percentage of insulin therapy among four groups showed statistical significance.2)The differences of HOMA-IR,ISI-OGTT,insulin secretion index with first phase and second phase among three groups(GDM, GIGT and NGT) showed statistical significance.2. Comparison of genotype and allele frequencies in subjects1) The results of sequencing were entirely consistent with the TaqMan allelic discrimination assay.2) Test for Hardy-Weinberg equilibrium:All SNPs were in Hardy-Weinberg equilibrium (p>0.05) in our study population.3) Genotype and allele analysis:The differences of genotype frequency of HNF1A rs1169288, GCK rs1799884, GCKR rs780094 between case group and control groups showed no statistical significance.4) Comparison of clinical and biochemical parameters in three genotypes of each locus.The differences of BG in GCT,3h BG in OGTT,1h Real insulin in OGTT, TG and hsCRP among three genotypes of GCKR rs780094 showed statistical significance. Others showed no statistical significance. 5) Risk factors of GDM by Logistic regression analysis:age,TG and hsCRP are independent risk factors for GDM, but not associated with three SNPs locus.6) Risk factors of hypertriglyceridemia during pregnancy by Logistic regression analysis:FPG nad hsCRP are independent risk factors for hypertriglyceridemia, but the GCKR rs780094 genotype with allele C is protective factor for TG.Conclusions1.GDM is associated with both insulin resistance and beta cell dysfunction.2.The polymorphisms of HNF1A rs1169288, GCK rs1799884 and GCKR rs780094 are not associated with the risk of GDM.3. Allele C of GCKR rs780094 is protetive factor for TG.