Investigation of the effects of FCGR2B and HLA-DRB1 gene variants on pemphigus vulgaris

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder caused by autoantibodies targeting intraepidermal desmosomal proteins desmoglein 3 (DSG3) and/or desmoglein 1 (DSG1). Its etiopathogenesis is complex, involving both genetic and environmental factors. Among genetic factors, immune-related genes within the HLA class II region particularly HLA-DRB1 variants have been identified as major genetic risk contributors in several studies. Additionally, FCGR2B, which encodes the inhibitory Fc gamma receptor IIb, plays a key role in downregulating B-cell activity, and its polymorphisms have been associated with autoimmune diseases such as systemic lupus erythematosus (SLE). This study aimed to investigate the potential influence of HLA-DRB1 alleles and the functional c.671T>C polymorphism in the FCGR2B gene on PV susceptibility. Genotyping was performed in 86 PV patients and 200 healthy controls using PCR-SSOP-Luminex for HLA-DRB1 typing and long-PCR-based Sanger sequencing for FCGR2B analysis. A total of 33 distinct HLA-DRB1 alleles were identified. HLA-DRB1*04:02 (adj_p = 6.71×10⁻²³; OR = 12.95; 95% CI: 7.40-24.57) and HLA-DRB1*14:01 (adj_p = 1.23×10⁻⁵; OR = 4.55; 95% CI: 2.35-8.74) were strongly associated with increased PV risk. Conversely, HLA-DRB1*11:01 (adj_p = 0.001; OR = 0.03; 95% CI: 0.00-0.31) and HLA-DRB1*16:01 (adj_p = 0.037; OR = 0.33; 95% CI: 0.10-0.75) showed a protective association. Notably, the combined presence of HLA-DRB1*04:02/14:01 (evaluated here for the first time) conferred a markedly elevated genetic risk (adj_p = 2.20×10⁻⁹; OR = 114.97; 95% CI: 6.86-1925.82). No significant difference was observed between groups regarding the FCGR2B c.671T>C variant. We believe that further study of class II receptors carrying HLA-DRB1*04:02/*14:01 alleles, which increase PV risk, will contribute to understanding the underlying mechanism.