TNFAIP3 Gene Polymorphisms in Three Common Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Primary Sjogren Syndrome—Association with Disease Susceptibility and Clinical Phenotypes in Italian Patients

Abstract

Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

The haplotypes of various TNF related genes associated with scleritis in Chinese Han

“…Moreover, we observed that the TT genotype frequency was lower, while the GT genotype frequency was higher in rs2230926, which is a nonsynonymous variant and leads to a change of the A20 protein at residue 127 from phenylalanine to cysteine [37]. Previous studies also reported similar observations concerning the risk association of scleritis with the G allele and GT genotype, such as RA [38], SLE [28,39], and primary immune thrombocytopenia (IPT) [40]. Furthermore, the expression of A20 mRNA was higher in rs2230926 GT genotype as compared to TT genotype carriers [41].…”

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents

“…4 Previous studies have related to the IFIH1, TNFAIP3, and STAT4 polymorphisms with a variety of inflammatory and autoimmune disorders such as multiple sclerosis, type 1 diabetes, psoriasis, inflammatory diseases, and SLE. [18][19][20][21][22][23] IFIH1 is found in various immune system cells and is involved in autoimmune disorders such as SLE. 24 IFIH1 increased IFN production by activation of NF-kB, IFNregulatory factors 3 and 7.…”

Musculoskeletal Manifestations in Sjogren’s Syndrome: An Orthopedic Point of View

“…An additional similarity was encountered regarding another central inflammatory mediator, the TNF-a. Ciccacci et al studying the role of TNF-a inducible protein 3 (TNFAIP3), an inflammation down-regulating gene, reported its pathogenetic role in all three diseases [ 53 ].…”