TRAF5 and TRAF3IP2 Gene Polymorphisms Are Associated with Behçet's Disease and Vogt-Koyanagi-Harada Syndrome: A Case-Control Study

Abstract

BackgroundTRAF5 and TRAF3IP2 have been reported to be associated with several autoimmune diseases. Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two autoimmune uveitis entities whereby both genetic and environmental factors are thought to be involved.ObjectiveThe role of TRAF5 and TRAF3IP2 in BD and VKH has not yet been reported and was therefore the subject of this study.MethodsThe study included 789 BD patients, 940 VKH patients and 1601 healthy unrelated individuals. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or TaqMan® SNP Genotyping Assay. Real-Time PCR was used to detect mRNA expression from PBMCs obtained from healthy controls with (n = 22) or without (n = 79) stimulation. Levels of TNF-α, IL-6 and IL-8 in culture supernatants were measured by ELISA (n = 22).ResultsThree SNPs (rs6540679, rs12569232, rs10863888) of TRAF5 and rs13210247 of TRAF3IP2 were significantly associated with Behçet's disease and VKH syndrome (corrected P values ranging from 9.45×10−12 to 0.027). TRAF3IP2 rs33980500 and rs13190932 were not polymorphic in Han Chinese. Following stimulation by lipopolysaccharide (LPS), carriers of the GG genotype of rs6540679/TRAF5 had a higher TRAF5 mRNA expression (p = 0.004) and an increased TNF-α (p = 0.0052) and IL-6 (p = 0.0014) level compared with AA and AG genotype carriers.ConclusionThis study provides evidence that TRAF5 and TRAF3IP2 genes are involved in the development of BD and VKH syndrome. Functional research suggested that TRAF5 gene polymorphisms may regulate TRAF5 expression and downstream inflammatory cytokines such as TNF-α and IL-6.

Association of a PDCD1 Polymorphism With Sympathetic Ophthalmia in Han Chinese

“…HaploView 4.2 was used to screen the candidate SNPs through a r 2 critical value of 0.8, as well as a minor allele frequency (MAF) larger than 0.05. Twenty-four SNPs from 19 genes were identified and included: one SNP (rs231775) of CTLA-4, 10 one SNP (rs2227981) of PDCD1, 11 one SNP (rs7574865) of STAT4, 12 one SNP (rs763780) of IL-17F, 13 one SNP (rs4754) of OPN, 14 one SNP (rs9494885) of TNFAIP3, three SNPs (rs310230, rs310236, rs310241) of JAK1, 16 one SNP (rs2301436) of FGFR1OP, 17 one SNP (rs755622) of MIF, 18 two SNPs (rs12569232, rs6540679) of TRAF5, 19 one SNP (rs13210247) of TRAF3IP2, 20 one SNP (rs17728338) of TNIP1, 20 one SNP (rs2488457) of PTPN22, 21 one SNP (rs76481776) of miR-182, 22 one SNP (rs3212227) of IL-12B, 23 two SNPs (rs442309, rs224058) of ADO-ZNF365-EGR2, 24 two SNPs (rs78377598, rs117633859) of IL23R-C1orf141, 24 one SNP (rs6498169) of CLEC16A, 25 and one SNP (rs4703863) of AGT10 (Table 1). 26 HLA typing was not performed in our SO patients.…”

“…1,9 In view of the similarities concerning the HLA disease association and the clinical similarities between SO and VKH, we decided to investigate whether associations found between VKH and a variety of non-HLA genes might also affect disease susceptibility for SO. Earlier reports describing a significant association between certain single nucleotide polymorphisms (SNPs) with VKH disease were identified and resulted in a total of 24 SNPs in 19 genes encoding for CTLA-4, 10 PDCD1, 11 STAT4, 12 IL-17F, 13 OPN, 14 TNFAIP3, 15 JAK1, 16 FGFR1OP, 17 MIF, 18 TRAF5, 19 TRAF3IP2, 19 TNIP1, 20 PTPN22, 21 miR-182, 22 IL-12B, 23 ADO-ZNF365-EGR2, 24 IL23R-C1orf141, 24 CLEC16A, 25 and AGT10. 26 Of these 24 SNPs, only an SNP located in PDCD1 was shown to be associated with SO, which confirms the hypothesis that both diseases, although sharing some features, are separate clinical entities mediated via different immunopathological pathways.…”

Molecular Genetic Advances in Uveitis

“…93 The interaction of CD40 with CD40L is regulated by tumor necrosis factor receptorassociated factor (TRAF), and recent studies showed that three SNPs in TRAF5 including rs6540679, rs12569232, and rs10863888, and rs13210247 in TRAF3IP2 were associated with BD and VKH syndrome. 94 Additionally, increased expression of TRAF5 and increased production of TNF-α and IL-6 were found in individuals carrying the risk genotype of TRAF5 rs6540679. 94 Most recently, Hou et al 13 performed a GWAS in a group of 1538 VKH patients and 5603 unaffected individuals and found an association between non-HLA genes including IL-23R-C1ORF141 and ADO/ ZNF365/EGR2 with VKH syndrome.…”

“…94 Additionally, increased expression of TRAF5 and increased production of TNF-α and IL-6 were found in individuals carrying the risk genotype of TRAF5 rs6540679. 94 Most recently, Hou et al 13 performed a GWAS in a group of 1538 VKH patients and 5603 unaffected individuals and found an association between non-HLA genes including IL-23R-C1ORF141 and ADO/ ZNF365/EGR2 with VKH syndrome. The five non-HLA genes were all found to be expressed in human iris tissue.…”

Classification of inflammatory skin diseases: A proposal based on the disorders of the three-layered defense systems, barrier, innate immunity and acquired immunity

“….Behçet's disease has been classified as an autoinflammatory disorder[25,26]. Two large genome-wide association studies (GWASs) reported the association between Behçet's disease and the single nucleotide polymorphism (SNP) of IL-10, IL-23R/ IL-12RB2, TRAF5, and TRAF3IP2 genes[27][28][29]. Pyoderma gangrenosum, characterized by sterile neutrophilic infiltration of the skin and other organs, is one of the clinical manifestations of a monogenic autoinflammatory disease, pyogenic arthritis, pyoderma gangrenosum, and cystic acne (PAPA) syndrome[22], in which CD2BP1 mutation results in the activation of the NLRP3 inflammasome[24].…”