Behcet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behcet's disease. Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behcet's disease in a cohort of 152 Behcet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology. We identified genetic associations between Behcet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 × 10-5, 1.0 × 10-4, 3.0 × 10-4, 1.5 × 10-3, and 5.8 × 10-3, respectively). Among the associated SNPs, the Behcet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein. Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behcet's disease. These findings will help to better understand the pathogenesis of Behcet's disease and identify novel targets for therapeutic intervention.

https://link.springer.com/content/pdf/10.1186%2Far2695.pdf

Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study

Objective To review the progress in the field of MHC-related genetic susceptibility to Behcet's disease (BD). Method Systematic review of the English literature between 1 January 1980 and 31 January 2010 using Medline. Case-control, population-based, observational cohort studies investigating the association between BD and HLA-B*51 subtypes, classical and non-classical HLA alleles and other HLA-related genes were selected. The geographical distribution of BD and these susceptibility genes was also taken into consideration. Case and familial case reports were excluded except for case series with more than two patients. Results Ninety articles plus 17 obtained from other sources were included in the systematic review. We have found high evidence that a core component of genetic susceptibility to BD is within the MHC region being primarily related to an HLA-B*51 subtype: HLA-B*5101/B*510101. Moreover, HLA-A*26, HLA-B*15, HLA-B*5701 and TNF-α -1031C were independently associated with BD. Data suggest that other HLA (HLA-C, HLA-DR) and HLA-related [MHC Class I chain-related gene A (MIC-A), TNF-α] genes may play a role in BD co-susceptibility or pathogenesis. Finally, the distinctive geographical distribution of BD suggested an evolutionary selection of HLA-B*51 subtypes as the major susceptibility factors for BD. Conclusion Further studies must be addressed to clarify the functional relevance of the different genes found to be associated with disease susceptibility and the potential interactions between genes located within and outside the MHC region.

Genetic susceptibility to Behçet's disease: role of genes belonging to the MHC region

Aim MicroRNA-146a (miR-146a) is involved in certain immune-mediated diseases. Transcription factor Ets-1 strongly affects miR-146a promoter activity and directly regulates miR-146a expression. This study was performed to investigate the association of miR-146a and Ets-1 gene polymorphisms with Behcet9s disease (BD) and Vogt–Koyanagi–Harada (VKH) disease in a Chinese Han population. Methods A total of 809 patients with BD, 613 patients with VKH and 1132 normal controls were genotyped for miR-146a/rs2910164, rs57095329 and rs6864584, Ets-1/rs1128334 and rs10893872 using a PCR restriction fragment length polymorphism assay. miR-146a expression was examined in peripheral blood mononuclear cells (PBMCs) by real-time PCR. Cytokine production by PBMCs was measured by ELISA. Results A significantly decreased frequency of the homozygous rs2910164 CC genotype and C allele was observed in patients with BD compared with controls (p c a =1.24×10 −5 , OR 0.61; p c a =1.33×10 −4 , OR 0.75, respectively). MiR-146a expression in GG cases was 2.45-fold and 1.99-fold higher, respectively, than that in CC cases and GC cases. There was no association of the other four single nucleotide polymorphisms (SNPs) with BD. There was also no association of these five SNPs with its main clinical features. No associations were found with the five SNPs tested or with its clinical manifestations in VKH disease. Interleukin (IL)-17, tumour necrosis factor (TNF)α and IL-1β production from rs2910164 CC cases was markedly lower than that in GG cases. No effect of genotype was observed on IL-6 and monocyte chemoattractant protein (MCP)-1 production and IL-8 expression was slightly higher in CC cases. Conclusions Our study identified a strong association of rs2910164 of miR-146a with BD in a Chinese population and decreased expression of miR-146a and certain proinflammatory cytokines in individuals carrying the CC genotype.

https://ard.bmj.com/content/annrheumdis/early/2012/12/24/annrheumdis-2012-201627.full.pdf?annrheumdis-2012-201627v1%3Bannrheumdis-2012-201627v1=

MicroRNA-146a and Ets-1 gene polymorphisms in ocular Behçet's disease and Vogt–Koyanagi–Harada syndrome

Pathergy is the term used to describe hyper-reactivity of the skin that occurs in response to minimal trauma. A positive skin pathergy test (SPT), characterised by erythematous induration at the site of the needle stick with a small pustule containing sterile pus at its centre, is among the criteria required for a diagnosis of Behcet's disease (BD) and in certain population has been shown to be highly specific for this condition. Problems with standardising the induction manoeuvre for the SPT as well as the method of assessment of the response have limited the usefulness of the SPT in the clinical setting. Extensive investigation into histopathological and immunological aspects of pathergy has led to a number of hypotheses relating to the aetiology of the skin pathergy reaction and the disease itself, but the cause is considered to be unknown. Pathergy lesions, the development of new skin lesions or the aggravation of existing ones following trivial trauma, are also reported in pyoderma gangrenosum and has been noted in other neutrophilic dermatoses such as Sweet's syndrome. The response of such patient groups to the systematic application of the SPT has not been described. We propose that a new way of considering the pathergy reaction is to see it as an aberration of the skin's innate reactivity from a homeostatic reactive mode closely coupled to tissue healing to an abnormal destructive/inflammatory mode. Our understanding of BD and other similar conditions would profit by more detailed mechanistic knowledge of skin homeostasis to minimal trauma in both health and disease through a more structured and systematic use of the SPT.

The skin pathergy test: innately useful?

Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in Behcet's disease (BD). T helper (Th) cells have a central role in modulating immune responses. Traditionally, BD is regarded as a Th1-mediated inflammatory disease. Recently, Th17 cells were identified as a new subset of Th cells unrelated to Th1 or Th2 cells, and several cytokines are involved in regulating their activation and differentiation. Naive murine CD4+ Th can be induced to differentiate towards Th1, Th2, Th17 and Treg phenotypes according to the local cytokine milieu. The committed cells are characterised by expression of specific transcription factors, T bet for Th1, GATA-3 for Th2, Foxp3 for Tregs and RORγt (RORγt/RORC) for Th17 cells. It has been demonstrated that the skewing of murine Th towards Th17 and Treg is mutually exclusive. Th17 cells regulate inflammation via production of distinct cytokines such as interleukin (IL)-17. There is growing evidence that Th17 cells are pathological in many human autoimmune and inflammatory diseases, leading to intense interest in defining their origins, functions and developing strategies to block their pathological effects. Evidence from human disease such as BD suggests that specialised antigen-presenting cells drive their in vivo development. Knowledge of how Th17 cells interact with other immune cells is limited, but recent data suggest that Th17 cells may not be subject to strict cellular regulation by T regulatory cells. Notably, Th17 cells and Treg cells appear to share common developmental pathways and both cell types retain significant plasticity. Herein, we will discuss the molecular and cellular regulation of Th17 cells with an emphasis on BD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of BD.

Jihene Lacheb

Papers

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease.