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 center dot 75, 95% confidence interval (CI) = 6 center dot 5-79; P < 0 center dot 0001], HLA-B*15:03 (OR = 12 center dot 15, 95% CI = 3 center dot 7-50 center dot 7; P < 0 center dot 0001), HLA-C*16:02 (OR = 6 center dot 53, 95% CI = 3-14; P < 0 center dot 0001), HLA-A*68:02 (OR = 3 center dot 14, 95% CI = 1 center dot 1-8 center dot 9; P < 0 center dot 01) were found to be associated with Behcet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3 center dot 39, 95% CI = 0 center dot 9-18 center dot 9; P = 0 center dot 04 for both). By contrast, HLA-A*03:01 (OR = 0 center dot 13, 95% CI = 0-0 center dot 8; P = 0 center dot 01) and HLA-DPB1*17:01 were found to be protective (OR = 0 center dot 27, 95% CI = 0 center dot 06-1 center dot 03; P = 0 center dot 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 center dot 98, 95% CI = 1 center dot 06-8 center dot 3; P = 0 center dot 01). In Egyptian Behcet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.