Association of Type 2 Diabetes Related SNPs with Predisposition of Gestational Diabetes Mellitus in Bangladeshi Women

Abstract

Background: Recent advances in genetic studies have revealed a number of susceptible loci for Type 2 diabetes mellitus (T2DM). In this study, we attempted to analyze the independent effect of variants in some of these loci on Gestational Diabetes Mellitus (GDM). The association of single nucleotide polymorphisms (SNPs) with the susceptibility of GDM was studied in a group of Bangladeshi women. Methods: Ten T2DM-related SNPs from six loci were selected. In this case-control study, 219 subjects with GDM and 286 subjects with normoglycemic controls were genotyped for the selected SNPs by PCR-RFLP, T-ARMS, and TaqMan™ allelic discrimination assay methods. Genotyping results were confirmed by DNA sequencing and replicated TaqMan™ assay. We analyzed the allele and genotype distribution between the cases and controls. The associations between SNPs and GDM were examined by logistic regression with five different genetic models adjusted for family history of diabetes (FHD) and gravidity. The cumulative associations of the target SNPs and the confounding variables with GDM were analyzed by interaction analyses. Results: We examined the effects of SNPs from CDK5 Regulatory Subunit Associated Protein 1-Like1(CDKAL1), Fat mass and obesity associated gene (FTO), Heat Shock Protein Family A (Hsp70) Member 1 Like (HSPA1L), Peroxisome proliferator-activated receptor gamma (PPARG), Transcription factor 7 like 2 (TCF7L2), and Wolfram syndrome 1 (WFS1) on the risk of GDM, with odds ratios ranging from 0.58 to 2.09. The CDKAL1 variants, rs7756992 (OR=1.6, P=0.02) and rs7754840 (OR=2.09, P=0.047), and the TCF7L2 rs12255372 (OR= 1.44, P=0.046) were significantly associated with the susceptibility of GDM. However, no significant association was detected between SNPs from FTO, HSPA1L, PPARG, and WFS1 with GDM. The risk alleles containing (CG) haplotype of the CDKAL1 gene variants, rs7756992 and rs7754840, conferred significant (P=0.032) disease susceptibility with an odds ratio of 1.43 (1.03-1.98). Concomitant presence of the risk alleles of these SNPs and positive FHD in any pregnant woman increased the chance of developing GDM by 1.5 to 4.8 folds. Significant increase in the susceptibility of GDM resulted from the CDKAL1 rs7756992 (OR=3.08, P=0.038) and TCF7L2 rs10885406 (OR=3.42, P=0.015). The synergistic effect of risk alleles of these SNPs and multigravidity increased the odds of xxv GDM by more than 1.5 folds in different genotypes, but a significant increase was revealed from the interaction analyses for FTO rs8050136 (P=0.0068). Conclusion: Several SNPs related to T2DM were associated with the risk of GDM through genotypic effects alone or interactions with the family history of diabetes and gravidity. These findings do not indicate to a single significant T2DM gene linked to GDM, but they do support the idea that T2DM is causally linked to GDM through several T2DM susceptibility genes and interactions with other factors. These associations also provided the possibility of potential markers for prediction of GDM and T2DM in Bangladeshi women.