The genetics of Behçet’s disease in a Chinese population

Abstract

Behçet’s disease is defined as a multisystemic inflammatory disease. Although the precise pathogenesis and etiology is still a mystery, accumulating evidence shows that genetic variants of immune-related genes have a profound influence on the development of Behçet’s disease. To explore the genetic factors for Behçet’s disease, our group investigated the association of Behçet’s disease with multiple immune response genes and has identified multiple Behçet’s disease-related immunoregulatory pathways in the Chinese Han population. A large number of gene polymorphisms were studied including STAT4, IL23R, CD40, CCR1/CCR3, STAT3, OPN, IL17, JAK2, MCP-1, CTLA4, PD-1, PD-L1, PD-L2, TGRBR3, CCR6, PTPN22, FCRL3, IRF5, SUMO4 and UBAC2. Significant associations were found between Behçet’s disease and STAT4, IL23R, CD40, CCR1/CCR3, STAT3, MCP-1, TGFBR3, FCRL3, SUMO4, UBAC2. These genetic predisposition studies support an important role for both lymphocyte differentiation as well as ubiquitination pathways. These findings are helpful in elucidating the pathogenesis of Behçet’s disease and hopefully will allow the development of novel treatment regimes.

Keywords

Behçet’s disease / SNPs / immune gene / genetic study

Introduction

Behçet’s disease, sometimes referred to as Silk Road disease, is a rare immune-mediated systemic vasculitis that often presents with the classical triad that includes oral aphthae, genital ulcers, and recurrent uveitis with hypopyon [1]. It usually affects individuals in their twenties or thirties. Epidemiologic investigations suggest that the distribution of Behçet’s disease presents a distinct geographic pattern along the old Silk Route [2,3]. Behçet’s disease is most common in Mediterranean countries, the Middle East, China and Japan, but is rare in the United States and Europe [4,5]. Globally, males are affected more frequently than females [6]. Our previous studies identified Behçet’s uveitis as one of the most common seen uveitis entities in China [5]. The prevalence rate of Behçet’s disease was estimated as 42/10 000 (95% CI, 34–51/10 000) in Istanbul, Turkey and 7–8.5/100 000 in Japan [7].

The pathogenesis and etiology of Behçet’s disease have not yet been fully clarified. Recent findings indicate that Behçet’s disease is an autoinflammatory disease possibly triggered by an aberrant response to infectious stimuli [8]. Significant progress has been made in identifying the contribution of the genetic background to disease development. The present article overviews an update on the genetics etiology or pathogenesis of Behçet’s disease in the Chinese Han population (Table 1).

Genes responsible for the immune response: HLA-B51, IRF5, PTPN22

The HLA complex is a multigene family on chromosome 6p21.3 in humans that encodes molecules critical to self/altered-self/non-self discrimination. It helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders and acts against bacteria and viruses in the body.

Our study investigated the association of HLA-B51 variants with Behçet’s disease in Chinese patients and normal controls. The results showed that the frequency of HLA-B51 was significantly higher in patients with Behçet’s disease than that observed in normal controls in a Chinese Han population [9]. This observation is consistent with various reports in different ethnic cohorts [10,11]. Although HLA-B51 is the highest risk factor for Behçet’s disease, its contribution was estimated to be only 19% for the overall genetic susceptibility to Behçet’s disease [12]. This observation may be explained by the fact that the frequency of HLA-B51 in Behçet’s disease is approximately 60% [13]. These data suggest that other genetic susceptibility loci are also involved.

IRF5, encoding a member of the interferon regulatory factor (IRF) family, has a critical role in virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. We recently investigated the association of SNPs rs2280714 and rs752637 in IRF5 with Behçet’s disease. However, we failed to find any association of IRF5 gene polymorphisms with Behçet’s disease [14], which is inconsistent with associations reported in other autoimmune diseases such as systemic lupus erythematosus (SLE) [15], inflammatory bowel disease (IBD) [16], rheumatoid arthritis (RA) [17] and multiple sclerosis (MS) [18].These results could be explained by the fact that the etiology and pathogenesis of Behçet’s disease may be different from those of the other autoimmune diseases.

The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene maps to chromosome 1p13.3-p13.1 and encodes a member of the non-receptor class 4 subfamily of the protein-tyrosine phosphatase family. The encoded protein is a lymphoid-specific intracellular phosphatase that associates with the molecular adapter protein Casitas B-lineage Lymphoma (CBL) and may be involved in regulating CBL function in the T cell receptor signaling pathway. Its mutations have been identified to be associated with a range of autoimmune disorders. In a recent study, we assessed the association between PTPN22 polymorphisms (rs2488457, rs1310182 and rs3789604) and Behçet’s disease in two Chinese Han populations [19]. No association was found between the investigated PTPN22 polymorphisms and Behçet’s disease. Previous studies showed PTPN22 polymorphisms were associated with a range of autoimmune diseases including Behçet’s disease in UK population [20]. These observed discrepancies may partially be explained by the different mechanisms involved in the pathogenesis of different autoimmune diseases and genetic heterogeneity for Behçet’s disease in different ethnic cohorts.

Co-stimulatory molecules: CTLA4, CD40, PD-1, PD-L1, PD-L2

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), also known as CD152 (Cluster of differentiation 152), is located on human chromosome 2q33 and is a member of the CD28 gene family. It is a key negative regulator of T lymphocytes and is expressed predominantly in activated and regulatory T lymphocytes. Our study investigated the association of CTLA4 gene polymorphisms (-1661A/G, -318C/T, + 49G/A, and CT60) with Behçet’s patients and normal controls [21]. We were not able to find an association between CTLA4 gene polymorphisms and Behçet’s disease, which is consistent with earlier studies reported by Zhang et al. [22] and Bye et al. [23], but in disagreement with a Tunisian study [24]. These data suggest a genetic heterogeneity concerning the association between CTLA4 gene polymorphisms and Behçet’s disease in different ethnic cohorts.

CD40 is a co-stimulatory protein found on antigen presenting cells and is required for their activation. It interacts with its ligand (CD40L), conveys signals regulating several immune processes such as priming of CD4⁺ and CD8⁺ T cells, and activation of antigen presenting cells and macrophages [25]. In a recent study, we examined the association of SNPs rs4810485 and rs1883832 in CD40 with Behçet’s disease [26]. The results suggest that the TT genotypes of rs4810485 and rs1883832 may be predisposing genotypes for Behçet’s disease, and that the rs4810485 GT genotype may be a protective genotype for Behçet’s disease. This result is inconsistent with earlier results reported by Raychaudhuri et al. in European patients with rheumatoid arthritis (RA) [27]. The discrepant result suggests a different gene predisposition to both Behçet’s disease and RA.

Programmed cell death 1 (PD-1) gene, located in chromosome 2q37.3, is one of non-human leucocyte antigen genes. It plays an important role in the regulation of the immune response [28]. PD-1 and its ligands belong to the CD28:B7 family. The ligands for PD-1 gene were programmed cell death-1 ligand 1 (PD-L1) and PD-L2. Interaction of PD-1 with its ligands inhibits T cell receptor-mediated proliferation and cytokine production. Our recent study examined the genotype of four SNPs, rs2227981 and rs10204525 of PD-1, rs1970000 of PD-L1 and rs7854303 of PD-L2, both in Behçet’s patients and healthy controls [29]. The results revealed no significant differences in the genotype and allele frequencies of PD-1 and PD-L1, PD-L2 between the Behçet’s patients and controls, which is in disagreement with observations in other autoimmune diseases in different ethnic groups [30-32]. These data suggest that the etiology and pathogenesis of Behçet’s disease may be different from other autoimmune diseases.

Relevant genes for Th1 differentiation: CCR1/CCR3, STAT4, OPN

C-C chemokine receptor type 1 (CCR1) and C-C chemokine receptor type 3 (CCR3) encode the chemokine receptor belonging to the G protein-coupled receptor super family. These receptors play an important role in the accumulation and activation of inflammatory cells [33–35]. We recently conducted a two-stage case control study for 26 SNPs to explore the relationship of the CCR1/CCR3 locus with Behçet’s disease in the Chinese Han population [36]. The association and conditional analysis showed that multiple variants, located in 3′ UTR, 5′ UTR region of CCR1 or 5′UTR of CCR3, were associated with Behçet’s disease. Haplotype analysis identified three associated haplotypes: H3 (GTGAC), H6 (CCATTA) and H9 (CGA). These results are consistent with a study reporting that CCR1 rs7616215, located in ~38 kb from the 3′ UTR of the CCR1, is associated with Behçet’s disease [37]. Our result also revealed a significantly increased expression of CCR1 and CCR3 in CT genotype individuals for SNP rs13092160. eQTLs database analysis revealed that the associated SNP rs13092160 is present in the eQTLs database, indicating that the variant associated with Behçet’s disease could potentially alter the amount of mRNA/protein produced.

STAT4 is a transcription factor belonging to the Signal Transducer and Activator of Transcription protein family. It is required for the development of Th1 cells from naive CD4⁺ T cells and plays a role in the IFN-g production in response to IL-12. We reported that SNP rs7574865 GG genotype may confer susceptibility in male Behçet’s disease patients [38]. Additionally, we conducted a genome-wide association study in Chinese Han Behçet’s disease patients and found an associated locus at STAT4 for Behçet’s disease [39]. Functional studies indicated that the risk SNP rs897200 in the STAT4 gene is involved in the pathogenesis of Behçet’s disease maybe through an effect on STAT4 transcription and the production of IL17, but not IFN-g. These data suggested that the rs897200 polymorphism in STAT4 may contribute to the development of Behçet’s disease via the involvement of the Th17 pathway, but not the Th1 pathway.

Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP) or early T-lymphocyte activation (ETA-1). OPN enhances T cell survival and proliferation and promotes Th1 and Th17 responses during chronic inflammation. Our group examined the OPN serum level in patients with Behçet’s disease and the association of gene polymorphisms of OPN and its receptors with Behçet’s disease [40]. The results showed that the OPN level was significantly increased in the serum of active Behçet’s disease patients compared with inactive Behçet’s disease patients and controls. SNP analysis did not reveal an association between the tested SNPs of OPN and its receptors in Chinese Han patients with Behçet’s disease.

Relevant genes for Th17 differentiation: IL23R, JAK2, STAT3, IL17, CCR6, TGFBR3, MCP-1

Components of the interleukin-23 signaling pathway, such as IL23R, IL17, JAK2 and STAT3 and other Th17 differentiation related genes such as CCR6, TGRBR3, MCP-1, have been implicated in a variety of autoimmune diseases. Additionally, emerging evidence supports the role of IL23-driven Th17 cells in inflammation. Our group therefore investigated the association of these genes with Behçet’s disease in the Chinese Han population. The results showed that SNPs rs17375018, rs11209032 in IL23R [41] and STAT3 rs2293152 [42], but not IL17 [43] were associated with the susceptibility to Behçet’s disease. Two genome-wide association studies also confirmed the association of IL23R with Behçet’s disease [44,45]. The results further suggest the important role of the interleukin-23 signaling pathway in the development of Behçet’s disease.

We also evaluated the association of MCP-1, CCR6, TGRBR3 polymorphisms with Behçet’s disease [46-48]. The results showed that the MCP-1-2518 AA genotype and TGFBR3 rs1805110 CC genotype show a protective association with Behçet’s disease.

Other genes

A genome-wide association study in Turkish Behçet’s disease patients identified five associated loci/genes including UBAC2 [49]. We replicated the association of the five loci/genes with Behçet’s disease in a Chinese Han population using a two stage association study [50]. Our result showed that UBAC2 gene polymorphisms were also associated with Behçet’s disease in a Chinese Han population. Multiple SNPs including rs3825427, rs9517668, rs9517701 showed an association with Behçet’s disease. Functional analysis showed that the risk T allele of the promoter polymorphism rs3825427 had a significantly lower promoter activity than the non-risk G allele and a decreased expression of UBAC2 transcript variant 1 in peripheral blood mononuclear cells (PBMCs) and skin of normal controls carrying the risk T allele compared with that in individuals with the G allele. These results are consistent with a Turkish study which established and confirmed the genetic association between UBAC2 and Behçet’s disease, and identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression [51].

Small ubiquitin-like modifier 4 (SUMO4) is known to downregulate the transcription activity of nuclear factor kappa B (NF-κB), and is involved in a range of autoimmune diseases. We were the first to report an association between SUMO4 polymorphisms with Behcet’s disease in a Chinese population and showed a significantly increased frequency of the+ 438 C allele and a significantly decreased frequency of the AGAT haplotype in patients with Behcet’s disease [9]. Later studies in Tunisian and Korean patients confirmed our findings [52,53], suggesting that a ubiquitination pathway may be involved in the development of Behçet’s disease.

We also examined the association of Fc receptor-like 3 (FCRL3) four polymorphisms with Behçet’s disease in a Chinese Han population [54]. A significantly higher frequency of the G allele at the -110 A/G SNP was found in Behçet’s disease with ophthalmic manifestations compared with that observed in controls. Haplotype CGCG frequency was significantly higher in patients than in controls.

Conclusions

This review provides insight into the potential role of a certain genetic background in the pathogenesis of Behçet’s disease. Our research group identified multiple Behçet’s disease-associated pathways including co-stimulatory molecules, relevant genes for Th1 differentiation, interleukin-23 signaling pathway and ubiquitin-related pathway. Accompanied by the development and application of novel techniques to study the genetic variants and the renovating knowledge on pathogenesis of disease, we will be able to clearly gain the true pathogenic mechanisms and etiological agents participating in this disease and hopefully will be able to treat it in the near nature.

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