Association of PD-1 gene polymorphisms and serum soluble PD-1 levels with type 1 diabetes mellitus susceptibility in a Chinese Han cohort: a case-control study

Background The programmed cell death 1 (PD-1)/PD-L1 pathway plays a critical role in immune tolerance and has been implicated in type 1 diabetes mellitus (T1DM). However, the associations between PD-1 polymorphisms, circulating soluble PD-1 (sPD-1), and T1DM susceptibility remain unclear in Chinese populations. This study evaluated the relationships of PD-1 rs2227981 and rs2227982 variants and serum sPD-1 levels with T1DM risk. Methods 89 T1DM patients and 70 healthy controls were enrolled. Genotyping was performed using TaqMan assays. Serum sPD-1 levels were measured by enzyme linked immunosorbent assay (ELISA) in a subset (44 T1DM, 28 controls). Genetic associations were assessed using multivariable logistic regression adjusting for sex, age, uric acid (UA), and triglycerides (TG). Results Significant differences in allele and genotype distributions of rs2227981 and rs2227982 were observed between groups. After adjustment, rs2227981 was significantly associated with T1DM under recessive (adjusted OR = 0.160, P = 0.027) and codominant models (adjusted OR = 6.764, P = 0.024). Rs2227982 remained significantly associated under additive (adjusted OR = 1.770, P = 0.012), dominant (adjusted OR = 0.454, P = 0.039), recessive (adjusted OR = 0.449, P = 0.032), and codominant models (adjusted OR = 0.319, P = 0.012). In genotype–phenotype analysis, rs2227982 was associated with HbA1c levels ( P = 0.036). Serum sPD-1 concentrations were elevated in T1DM patients ( P = 0.013) but showed no correlation with glycemic parameters, autoantibody status, or PD-1 genotypes. Conclusions PD-1 rs2227981 and rs2227982 polymorphisms are associated with T1DM susceptibility in a Chinese Han cohort. Rs2227982 may be linked to glycemic phenotype, while elevated sPD-1 levels suggest altered immune checkpoint regulation rather than reflecting short-term metabolic control. Larger and longitudinal studies are needed to confirm these findings.