A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases with complex genetic components. To identify a gene(s) susceptible to SLE, we performed a case-control association study using genome-wide gene-based single nucleotide polymorphisms (SNPs) in Japanese population. Here we report that an SNP (rs3748079) located in a promoter region of the inositol 1,4,5-triphosphate receptor type 3 ( ITPR3 ) gene on chromosome 6p21 was significantly associated with SLE in two independent Japanese case-control samples [ P = 0.0000000178 with odds ratio of 1.88, 95% confidence interval (CI) of 1.51–2.35]. This particular SNP also revealed associations with rheumatoid arthritis (RA) ( P = 0.0084 with odds ratio of 1.23, 95% CI of 1.05–1.43) and with Graves’ disease (GD) ( P = 0.00036 with odds ratio of 1.57, 95% CI of 1.22–2.02). We found the binding of NKX2.5 specific to the non-susceptible T allele in the region including this SNP. Furthermore, an SNP in NKX2.5 also revealed an association with SLE ( P = 0.0037 with odds ratio of 1.74, 95% CI of 1.19–2.55). Individuals with risk genotype of both ITPR3 and NKX2.5 loci have higher risk for SLE (odds ratio = 5.77). Our data demonstrate that genetic and functional interactions of ITPR3 and NKX2.5 play a crucial role in the pathogenesis of SLE.