Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus

Abstract

The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

“…More recently, this gene region has also been associated with SLE in two independent studies. 21,22 In Musone et al 22 three independent associations conferring risk were associated with SLE, including the two SNPs previously associated with RA. However, Graham et al 21 found two independent associations, one of which was previously associated with RA.…”

“…18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years. We genotyped SNPs from the genes: CD58 (rs12044852) which has been associated with multiple sclerosis; 8 STAT3 (rs3816769) which has been associated with CD; 7 IL1A (rs17561) and ERAP1, previously called ARTS1 (rs30187) which have been associated with AS; 15,17 MMEL1-TNFRSF14 (rs3890745), CDK6 (rs42041), the 7q23 gene desert (rs11761231), CCL21 (rs2812378), TRAF1/C5 (rs3761847), KIF5A(rs1678542) and CD40 (rs4810485), which have been associated with RA; 7,12,19 BANK1 (rs10516487), FAM167A previously called C8orf13 (rs13277113) and ITGAM (rs9888739) which have been associated with SLE [9][10][11]20 and STAT4 (rs7574865) and TNFAIP3 (rs6920220 and rs10499194) which have been associated with both RA and SLE 13,14,16,21,22 (See Table 1 for full gene names).…”

Shared susceptibility variations in autoimmune diseases: a brief perspective on common issues

“…This includes TNFAIP3, where it appears that at least one component of the RA risk is different from the SLE risk haplotype. [17][18][19] The shared risk factors appear to have unique overlaps between different autoimmune diseases. For example, the PTPN22 Arg620Trp that is sheared between several autoimmune diseases including T1DM and RA has been shown not to be a risk factor in MS, whereas in the present studies CD226 and CLEC16A variations are shared risk factors between MS and T1DM.…”

A20 takes on tumors: tumor suppression by an ubiquitin-editing enzyme

“…While only one missense coding allele has been identified thus far (in SLE), the wellestablished antiinflammatory functions of A20 in mice suggest that hypomorphic function or expression of A20 may contribute to the pathophysiology of these human conditions (24). Collectively, these findings suggest that subtle germline TNFAIP3 hypomorphisms may predispose individuals to chronic autoimmune diseases, whereas gross A20 deficiencies occurring somatically may contribute to lymphoma.…”

“…(SLE), rheumatoid arthritis, psoriasis, and celiac disease (24)(25)(26)(27)(28)(29). While only one missense coding allele has been identified thus far (in SLE), the wellestablished antiinflammatory functions of A20 in mice suggest that hypomorphic function or expression of A20 may contribute to the pathophysiology of these human conditions (24).…”