Association Of Single Nucleotide Polymorphisms 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. The incidence is continuously increasing in China. It has been indicated that GDM is associated with increased long-term complications in mothers and offspring. The specific pathogenesis of GDM is still unknown, but some studies confirmed that genetics may have effect on GDM. Additionally, researches indicated that GDM may share the same genetic factors with Type2diabetes mellitus to some content. Therefore, our aim of this study was to investigate the correlation between (CDKAL1rs7754840, SRR rs391300, CDKN2A/2B rs2383208, IGF2BP2rs4402960, MTNR1B rs10830963, GCK rs4607517) and GDM in a Chinese population. The single nucleotide polymorphism of SRR is firstly investigated in GDM population.Methods1. SubjectsFrom march2006to march2011, All pregnant Chinese women were screened for GDM between24and28weeks with a50g glucose challenge test in peking union medical college hospital. Plasma glucose1hour after intake of glucose more than7.8mmol/l was defined as GCT positive (GCT+). GCT+women were then administered a100g oral glucose tolerance test. According to the ADA criteria,1764pregnant women were included in the study:725with GDM,768with NGT and271who 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. Genotyping of the six SNPs (CDKAL1rs7754840, SRR rs391300, CDKN2A/2B rs2383208, IGF2BP2rs4402960, MTNR1B rs10830963, GCK rs4607517) was performed using Taqman allelic discrimination assays. The genotyping results were verified by direct sequencing.Results1. Comparison of clinical and biochemical parameters 1) The age, systolic blood pressure (SBP), diastolic blood pressure (DBP), white blood cell counting (WBC), platelet counting (PLT), glucose and real insulin during OGTT, glycosylated hemoglobin (HbA1c),triglyceride(TG), hypersensitivity C reaction protein (hs-CRP) showed statistical significance between cases (GDM) and controls (NGT+GCT-)2) The level of insulin resietance index (HOMA-IR) and beta cell function index (HOMA-B and insulin AUC) were significantly different between the two groups.2. Comparison of SNPs, GDM and biochemical parameters1) The test of reliability:The results of sequencing were consistent with the TaqMan allelic discrimination assay, which indicated that the results of genotyping were reliable.2) Test of Hardy-Weinberg equilibrium:All six SNPs were in Hardy-Weinberg equilibrium (p>0.05) in the case and control groups.3) Results of genotype and allele distribution:We found that the rs4402960(OR=1.207,95%CI=1.029-1.417, p=0.021), rs2383208(OR=1.242,95%CI=1.077-1.432, p=0.003) and rs391300(OR=1.202,95%CI=1.020-1.416, P=0.028) were statistically associated with GDM. In addition, the effect was greater under a recessive model in rs391300(OR=1.820,95%CI=1.226-2.701, p=0.003).4) Comparison of clinical and biochemical parameters:The results indicated that rs2383208(b=0.055, p=0.034), rs391300(b=0.059, p=0.028) and rs10830963(b=0.062,p=0.019) showed positive association with FPG. The risk alleles of rs2383208(b=20.085, p=0.003), rs4402960(b=20.057, p=0.046) and rs10830963(b=20.096, p=0.001) were associated with HOMA-B, while rs7754840(b=20.080, p=0.007) was associated with decrease in insulin AUC5) The joint effect of SNPs:Compared to the effect of three single SNPs, the results indicated an additive effect of three risk alleles on the risk of developing GDM with an OR of1.196per allele (OR=1.196,95%CI=1.092-1.309, P=1.08×10-4).Conclusions1. GDM may share the same genetic factors with T2DM to some content, for insulin resistance and beta cell dysfunction.2. The polymorphisms of rs4402960, rs2383208and rs391300were statistically associated with GDM.3. The polymorphisms rs2383208, rs391300and rs10830963showed positive association with FPG while the risk alleles of rs2383208, rs4402960and rs10830963were associated with HOMA-B. At the same time rs7754840was associated with decrease in insulin AUC during a100g OGTT given at the time of GDM diagnosis.