Genetics and Epigenetics of Behçet’s Disease

For our genetic analyses of Behçet’s disease, we have built a unique investigative consortium that includes physicians and researchers in Turkey where Behçet’s disease is most common, Italy, Germany, The Netherlands, Japan, and Korea. Using extensive genotyping and imputation analysis we performed an exhaustive genetic study extending over ~30,000 genetic variants in the HLA region in Behçet’s disease and identified multiple independent susceptibility loci replicated in two ethnically divergent cohorts. Importantly, published in Nature Genetics recently, this paper brought attention to non-coding inter-genic regions within the HLA, and suggests that the association with a genetic variant between the HLA-B and MICA genes is more robust and in fact might explain the genetic risk previously attributed to HLA-B*51 in our disease cohorts. Other work from our lab, which followed up on the first GWAS study in Behçet’s disease that we had previously performed, established a novel genetic association in the UBAC2 gene, and showed that the disease risk genetic variant in this locus is associated with altered UBAC2 expression. Our most recent publication in Behçet’s disease, in close collaboration with our colleagues in Turkey, was a comprehensive evaluation of the DNA methylome in CD4+ T cells and monocytes from patients compared to normal age, sex, and ethnicity matched controls. These studies identified a pattern of significant epigenetic aberrancies in patients involving multiple cytoskeletal remodeling genes critical in inflammatory cell migration and tissue invasion. Further, studying the same patients before and after disease remission, we demonstrated that reversal of these methylation changes underlies therapeutic response in this disease. Therefore, this first epigenetic study in Behçet’s disease uncovered specific novel epigenetic biomarkers and therapeutic targets, such as RAC1 and FSCN2 among others, which are involved in cytoskeletal actin polymerization and bundling that is crucial to filopodia and lamellipodia formation during tissue cell migration. Importantly, this study serves as proof of principle for utilizing similar epigenomic approaches, in specific cell subsets and well characterized cohorts of patients and controls, as a tool to make new discoveries related to the pathogenesis of immune-mediated diseases, and the identification of specific and testable novel therapeutic target molecules and pathways, and biomarkers for disease activity. 

Genetic association in the HLA region in Behçet's disease Genetic association in the HLA region in Behçet's disease (Source: Hughes et al. Nature Genetics 2013)