Genetics of Behçet’s disease

Abstract

Behçet’s disease (BD) is a multifactorial disease with a strong genetic background. Higher frequencies of patients with a positive family history for BD were reported from the Middle East and among patients who are HLA-B*51 positive or with juvenile disease onset. Sibling recurrence risk ratio (λs) was estimated as 11.4-52.5 in high prevalence regions. BD is strongly associated with a class I major histocompatibility complex (MHC) allele, HLA-B*51, and this association was confirmed in various ethnic groups. Distribution of HLA-B*51 allele in healthy population is suggested to play a role in the disease clustering in an area extending from the Mediterranean basin to Japan. The HLA-B*51-driven pathogenic mechanisms are still unknown, but weaker associations with other HLA-B (i.e., HLA-B*49 as protective and HLA-B*15, HLA-B*27, and HLA-B*57 as risk) and HLA-A (i.e., HLA-A*03 as protective and HLA-A*26 as risk) alleles, which are polymorphic at antigen-binding sites, suggest the importance of peptide binding in the pathogenesis. Identification of an epistatic interaction between certain ERAP1 haplotypes and HLA-B*51 supported further the important role of the endoplasmic reticulum peptidome. Accumulation of low-affinity peptides for loading on the antigen-binding groove of HLA-B*51 may affect their potential to fold properly and to present the peptides to CD8+ cells. Genome-wide association studies in different ethnic groups revealed several non-HLA polymorphisms increasing the susceptibility to BD. Most of these associations have immunoregulatory functions, and they are considered to be affecting the sensitivity to different environmental triggers as well as responsible for the pathergic activation of innate and adaptive immune responses as well as endothelial cells.