Homozygous AA Genotype of IL-17A and 14-bp Insertion Polymorphism in HLA-G 3'UTR Are Associated with Increased Risk of Gestational Diabetes Mellitus

Abstract

Gestational diabetes mellitus (GDM) is a common pregnancy complication characterized by hyperglycemia and insulin resistance, with unclear genetic mechanisms. The specific involvement of proinflammatory cytokines, including IL-17A, and the immuno-tolerogenic HLA-G remains poorly understood in GDM. We aimed to explore the associations of three polymorphisms, IL-17A -197G>A (rs2275913), IL-17RA -947A>G (rs4819554), and HLA-G 14-bp insertion/deletion (indel), with GDM risk in a Brazilian population. We conducted a case-control study (79 GDM cases and 79 controls). Genetic polymorphisms were analyzed using PCR-RFLP, with DNA extracted using the Salting-out procedure. Significant associations were identified between -197G>A rs2275913 and HLA-G 14-bp indel polymorphisms in both codominant and recessive models. The IL-17A rs2275913 AA genotype was associated with a nearly ten-fold increased risk of GDM in both the codominant (p = 0.021, OR 9.89, 95% CI: 1.63-59.92) and recessive models (p = 0.006, OR 9.33, 95% CI: 1.57-55.38). Similarly, the HLA-G 14-bp Ins/Ins genotype was associated with an increased risk in both the codominant (p = 0.026, OR 3.34, 95% CI: 0.98-11.41) and recessive models (p = 0.010, OR 4.20, 95% CI: 1.36-12.96). IL-17RA polymorphism showed no significant associations. The study findings highlight the potential genetic and immune factors associated with GDM, particularly the -197G>A rs2275913 and HLA-G 14-bp indel polymorphisms. Further functional characterization is warranted to uncover the mechanism of genotype-phenotype association.

Keywords: Gestational Diabetes Mellitus; HLA-G 14-bp insertion/deletion; IL-17A polymorphism; IL-17RA polymorphism; genetic association.

Figure 1

Mechanism of action of the SNPs IL-17A -197G>A rs2275913 and HLA-G 3′UTR 14-bp Insertion/Deletion in Gestational Diabetes Mellitus. AA genotype in the polymorphic loci IL-17A 197G>A rs2275913 causes a higher expression of IL-17, while the 14pb insertion in the 3′UTR in the HLA-G gene destabilizes mRNA causing a reduction in the expression of immunomodulatory HLA-G. This scenario increases the inflammatory profile characteristic of gestational diabetes mellitus with increased release of Th1/Th17 cytokines. Created in https://BioRender.com (accessed on 8 February 2025).