Behcet disease, new insights in disease associations and manifestations: a next-generation sequencing study.

Behcet disease is a multi-system disease associated with human leukocyte antigen (HLA) class I polymorphism. High-resolution next-generation sequencing (NGS) with haplotype analysis has not been performed previously for this disease. Sixty Egyptian patients diagnosed according to the International Study Group (ISG) criteria for Behcet disease and 160 healthy geographic and ethnic-matched controls were genotyped for HLA class I loci (HLA-A, B, C). For HLA class II loci (DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1), 40 control samples were genotyped. High-resolution HLA genotyping was performed using NGS and the results were analyzed. Clinical manifestations were oral ulcers (100%), genital ulcers (100%), eye (55%) and neurological (28%) and vascular involvement (35%). HLA-B*51:08 [odds ratio (OR) = 19.75, 95% confidence interval (CI) = 6.5-79; P < 0.0001], HLA-B*15:03 (OR = 12.15, 95% CI = 3.7-50.7; P < 0.0001), HLA-C*16:02 (OR = 6.53, 95% CI = 3-14; P < 0.0001), HLA-A*68:02 (OR = 3.14, 95% CI = 1.1-8.9; P < 0.01) were found to be associated with Behcet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3.39, 95% CI = 0.9-18.9; P = 0.04 for both). By contrast, HLA-A*03:01 (OR = 0.13, 95% CI = 0-0.8; P = 0.01) and HLA-DPB1*17:01 were found to be protective (OR = 0.27, 95% CI = 0.06-1.03; P = 0.02). We identified strong linkage disequilibrium between HLA-B*51:08 and C*16:02 and A*02:01 in a haplotype associated with Behcet disease. HLA-B*51:08 was significantly associated with legal blindness (OR = 2.98, 95% CI = 1.06-8.3; P = 0.01). In Egyptian Behcet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.