Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study

A case-control association study was conducted on the TNIP1 single nucleotide polymorphism (SNP) rs7708392 in 364 Japanese SLE patients, 553 RA patients and 513 healthy controls.Association of TNIP1 rs7708392C was replicated in Japanese SLE (allele frequency in SLE: 76.5%, control: 69.9%, P = 0.0022, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.13-1.74). Notably, the risk allele frequency in the healthy controls was considerably greater in Japanese (69.9%) than in Caucasians (24.3%). A tendency of stronger association was observed in the SLE patients with renal disorder (P = 0.00065, OR 1.60 [95%CI 1.22-2.10]) than in all SLE patients (P = 0.0022, OR 1.40 [95%CI 1.13-1.74]). Significant association with RA was not observed, regardless of the carriage of human leukocyte antigen DR β1 (HLA-DRB1) shared epitope. Significant gene-gene interaction between TNIP1 and TNFAIP3 was detected neither in SLE nor RA.Association of TNIP1 with SLE was confirmed in a Japanese population. TNIP1 is a shared SLE susceptibility gene in the Caucasian and Asian populations, but the genetic contribution appeared to be greater in the Japanese and Chinese populations because of the higher risk allele frequency. Taken together with the association of TNFAIP3, these observations underscore the crucial role of NF-κB regulation in the pathogenesis of SLE.TNFAIP3 (tumor necrosis factor α-induced protein 3) encodes a ubiquitin-editing protein, A20, known as an inhibitor of nuclear factor-κB (NF-κB). Several adaptor molecules are thought to associate with A20 and be involved in inhibition of NF-κB [1]. TNIP1 (TNFAIP3 interacting protein 1), also known as ABIN (A20-binding inhibitor of NF-κB)-1, is one such adaptor molecule binding to A20. TNIP1 mRNA is strongly expressed in peripheral blood lymphocytes, spleen and skeletal muscle, and the expression is also detected in kidney [2]. TNIP1 expression is induced by NF-κB, and in turn, overexpression of TNIP1 inhibits NF-κB activation by TNF [1]