KCNN3 genetic variants rs1218585 and rs1218584 are associated with spontaneous preterm birth in a Portuguese population

Spontaneous preterm birth (SPTB) is a major cause of neonatal morbidity and mortality worldwide. Although a genetic component has been implicated, specific variants remain poorly defined. The potassium calcium-activated channel subfamily N member 3 (KCNN3) gene encodes the SK3 potassium channel, which contributes to myometrial relaxation and uterine quiescence. This study aimed to assess the association between two KCNN3 variants (rs1218585 and rs1218584) and SPTB in a Portuguese postpartum women cohort. Genotyping was performed using iPLEX Gold technology, and logistic regression was applied under multiple inheritance models, with adjustments made to sociodemographic and lifestyle variables. Both variants showed a significant association with SPTB. The GA genotype of rs1218585 and the CG genotype of rs1218584 were associated with 3.67- and 3.00-fold increased odds of SPTB, respectively. Associations remained significant after adjustment and multiple testing corrections. Haplotype analysis also identified a minor allele combination (AG) associated with increased odds of SPTB. These findings support a role for KCNN3 variants in SPTB susceptibility and highlight the potential of SK3 potassium channels in preterm labour pathophysiology. Larger studies in diverse populations are warranted to validate these associations and clarify their potential clinical relevance.