Genetic links between SYNPR, CDH18, and PTGIS variants and gestational diabetes mellitus in an Iranian cohort

Abstract

Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy with a significant genetic component. Genetic variants in the SYNPR, CDH18, and PTGIS genes have been previously implicated in GDM risk in East Asian populations, but their role in Middle Eastern populations remains unexplored. This study aimed to investigate the association of specific polymorphisms in these genes with GDM susceptibility in an understudied Iranian cohort from the Mashhad metropolis, Razavi Khorasan Province. A case-control study was conducted involving 400 Iranian pregnant women (200 GDM cases and 200 healthy controls) recruited from the affiliated clinics of Mashhad University of Medical Sciences (MUMS). Six single nucleotide polymorphisms (SNPs)—rs1545458 and rs905941 (SYNPR), rs1344692 and rs11744487 (CDH18), rs6095547 and rs5602 (PTGIS)—were genotyped using the Amplification-Refractory Mutation System (ARMS-PCR) with quality control ensured by duplicate samples. Bonferroni correction was applied for multiple comparisons (significance threshold p < 0.0083). Associations with GDM risk were assessed using multivariate logistic regression adjusted for confounders. After adjustment for age, height, smoking, history of macrosomia, and family history of type 2 diabetes, several SNPs showed significant associations. In CDH18, rs11744487 was associated with GDM (AC vs. AA: OR = 0.327; 95% CI: 0.165–0.647, p = 0.001). In PTGIS, rs6095547 (CT vs. CC: OR = 3.839; 95% CI: 1.849–7.969, p < 0.001) and rs5602 (CT vs. CC: OR = 0.154; 95% CI: 0.067–0.356, p < 0.001) were significant, revealing both risk and protective alleles within the same gene. Haplotype analyses revealed increased GDM risk for specific haplotypes within SYNPR (AG), CDH18 (GA, AA), and PTGIS (TC). This study provides the first evidence for the involvement of the SYNPR, CDH18, and PTGIS loci in GDM susceptibility in an Iranian population. These findings validate previous reports in East Asians and highlight the importance of population-specific genetic risk scores. The paradoxical findings in PTGIS (rs6095547 risk vs. rs5602 protective) underscore the complex polygenic architecture of GDM.