Abstract
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.