Genetic interaction between genes involved in NF-κB signaling pathway in systemic lupus erythematosus

Recently, multiple genetic associations have been found between genes involved in nuclear factor-kappaB (NF-κB) signaling pathway and systemic lupus erythematosus (SLE) or other autoimmune diseases. This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population. Ten single-nucleotide polymorphisms (SNPs) in NFKB1, REL, inhibitor of κB-like (IκBL), IκB kinase β (IKBKB), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor a-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology. Single-marker genetic association analysis was performed, and additive and multiplicative interactions were analyzed. Associations of TNFAIP3 rs2230926 (p = 1.43 × 10−3) and TNIP1 rs10036748 (p = 4.33 × 10−3) with SLE were replicated in our study. Two other SNPs, NFKB1 rs28362491 and IκBL rs2071592, showed nominal evidence for association (p = 4.70 × 10−2 and p = 5.90 × 10−3, respectively) but these were not significant after applying Bonferroni correction. Additive interaction analysis revealed significant interaction between NFKB1 rs28362491 and TNFAIP3 rs2230926 (RERI = 0.98, 95%CI = 0.02-1.93; AP = 43.2%, 95%CI = 0.12-0.74). Significant multiplicative interaction was observed between NFKB1 rs28362491 and TNIP1 rs3792783 (p = 0.03). Our results provide evidence for gene-gene interactions, which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability.