African-Derived Genetic Polymorphisms in TNFAIP3 Mediate Risk for Autoimmunity

Abstract

The TNF α-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case–control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio = 1.6, p = 0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio = 0.31, p = 0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.

Expression of TNFAIP3 in intestinal epithelial cells protects from DSS- but not TNBS-induced colitis

“…Thus genetic variants that alter TNFAIP3 expression or activity might be expected to be associated with IBD. Genetic variants in or near the TNFAIP3 gene have been implicated in a number of human immune disorders, including celiac disease, diabetes, rheumatoid arthritis, psoriasis, and systemic lupus erythematosus (13,16,17,24,28). Although there have been modest IBD associations with TNFAIP3 in genome-wide association studies, results have not consistently identified strong genetic associations in this locus with IBD.…”

“…Although there have been modest IBD associations with TNFAIP3 in genome-wide association studies, results have not consistently identified strong genetic associations in this locus with IBD. Other studies of rare or coding variants in TNFAIP3 have found associations with IBD susceptibility (16,18). Decreased TNFAIP3 expression is one component of a five-gene signature that marks the severity of Crohn's disease and responses to therapy (1).…”

B cells from African American lupus patients exhibit an activated phenotype

“…Few risk alleles specific to African American SLE patients have been identified. The SNP rs5029953 in the TNFAIP3 locus is essentially represented in the African American population and confers an increased risk of SLE (42). TNFAIP3 codes for A20, which is a negative regulator of NF-κB signaling downstream of CD40 in B cells.…”

IRF5, PTPN22, CD28, IL2RA, KIF5A, BLK and TNFAIP3 genes polymorphisms and lupus susceptibility in a cohort from the Egypt Delta; relation to other ethnic groups

“…Almost all of the key components in 53 the immune system are involved in the disease pathogenesis 54 which is still largely unclear [2]. A lot of candidate-gene studies 55 were done till 2008 which identified only a handful of genetic loci 56 affecting SLE susceptibility [3], however, the genome wide associ- 57 ation studies (GWASs) have expanded these loci to nearly 40 vali-58 dated susceptibility loci [4]. 59 Clustering of most of these genetic associations outside MHC 60 can apparently be categorized into at least three major pathways 61 [5] (i) activation of toll-like receptor (TLR), type I interferon (IFN) 62 and NF-jB signaling (e.g., IRF5 [6], IRF7 [7], IRF8 [8], TNFAIP3 [9], 63 TNIP1 [6] and TLR8 [10]) (ii) clearance of apoptotic cells and 64 immune complexes (e.g., ITGAM [7], FccR [11]) (iii) multiple http://dx.doi.org/10.1016/j.humimm.2015.06.001 0198-8859/Ó 2015 American Society for Histocompatibility and Immunogenetics.…”