The presence of HLA-B51 and ERAP-1 variations in familial Behçet's disease patients and their relationship with clinical findings

Objective: HLA-B51 is the most well-established genetic factor associated with BS. Investigation of familial BS is important for understanding the genetic background of the disease. This study aimed to evaluate the relationship between HLA-B51 and the clinical characteristics of familial BS cases, as well as to determine whether ERAP1 influences disease phenotype. Methods: In this single-center, retrospective cross-sectional study, 11,560 BS patients were screened. A total of 713 patients with at least one first-degree relative diagnosed with BS and 1,744 sporadic cases were compared. Among 339 familial cases with known HLA-B51 status, 24 HLA-B51–positive families were selected for ERAP1 sequencing. Exons 2, 5, 6, 11 and 15 of ERAP1 were analyzed by Sanger sequencing. Associations were assessed using 2×2 contingency tables, odds ratios (ORs), 95% confidence intervals (CIs), and Fisher's exact test. Results: The mean age of familial BS patients was 50.0 ± 13.6 years, and sibling relationships were the most common (60%). Major organ involvement included ocular (36.9%), vascular (17.5%), neurological (4.6%), and gastrointestinal (2.2%) manifestations. Male patients showed more frequent major organ involvement. Familial BS had an earlier disease onset (<16 years, 25.1% vs 14.3%; p<0.001). Familial BS showed lower rates of genital ulcer, ocular, and vascular involvement, but a higher rate of pathergy positivity (p<0.001). HLA-B51 positivity was significantly higher in familial BS (70.8% vs 61.3%; p=0.008) but was not associated with specific organ involvement. No significant differences were observed in ERAP1 variants. Conclusion: Familial BS presents with earlier onset and higher HLA-B51 positivity but lower ocular and vascular involvement than sporadic BS. HLA-B51 alone does not determine organ-specific phenotype, suggesting contributions from additional genetic and environmental factors. Larger prospective studies are warranted to clarify the role of ERAP1 variants. Keywords: Behçet's syndrome, familial BS, HLA-B51, ERAP1, genetic epistasiS, uveitis, vascular involvement, discordant/concordant families