The Influence of PDCD1 (PD-1) and CD274 (PD-L1) Variants on Preeclampsia Risk, Severity, and Onset: A Single and Synergistic Genetic Analysis

Preeclampsia (PE) remains a leading cause of maternal and perinatal morbidity and mortality, with immunological dysregulation being a key factor in its pathogenesis. In this case–control study, we investigated the association of PDCD1 rs10204525 and CD274 rs4143815 polymorphisms with PE risk, severity, and onset in 560 Iranian women (280 patients and 280 controls). Carriers of the PDCD1 rs10204525 A allele had a significantly increased risk of PE, with odds ratios (OR) of 1.68 for the GA genotype and 2.60 for the AA genotype, particularly in severe PE. Similarly, the CD274 rs4143815 G allele (CG/GG genotypes) was associated with a 1.9–2.4-fold increased risk of severe PE. Analysis of combined genotypes revealed synergistic effects; notably, the combined genotypes demonstrated a synergistic effect: GG-GG raised the risk of early-onset PE by 5.1-fold, while AA-CG was associated with the highest PE risk (7.9-fold elevation). The GA-CG genotype combination was also strongly associated with severe preeclampsia, conferring a 4.6-fold increased risk. These findings underscore the important role of PDCD1/CD274 genetic variations in influencing both susceptibility to preeclampsia and the heterogeneity of its clinical presentation in women. This indicates that disruptions in immune checkpoint function may exacerbate disease severity and contribute to earlier onset. This study identifies potential genetic biomarkers for risk stratification and indicates that tailored immunomodulatory approaches might be beneficial in high-risk pregnancies. We need more functional research to elucidate underlying mechanism and make individualized solutions as effective as possible.