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

Abstract

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 genomewide 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.

Transcription Factor Binding Site Polymorphism in the Motilin Gene Associated with Left-Sided Displacement of the Abomasum in German Holstein Cattle

“…This SNP affects a NKX2-5 transcription factor binding site. The effect of NKX2-5 on gene expression has been previously described [15] and SNPs within NKX2-5 binding sites have been reported to be functional for complex genetic diseases as systemic lupus erythematosus, rheumatoid arthritis, and graves disease in man as the mutations lead to a reduced expression of the respective gene [16]. Therefore, FN298674:g.90T>C is presumably the reason for the reduced expression of MLN in GH cows carrying a C allele at this position.…”

Cardiac inositol 1,4,5-trisphosphate receptors

“…Thus the complete loss of IP 3 R-2 calcium release function, like IP 3 R-1, is compatible with life in humans. Currently, there are no known human diseases definitively linked to mutations in the IP 3 R-3 protein, however single nucleotide polymorphisms in the ITPR3 gene are associated with increased risk of type 1 diabetes [70] and systemic lupus erythematosus [71]. …”

ITPR3 gene haplotype is associated with cervical squamous cell carcinoma risk in Taiwanese women

“…The rationale for choosing these 2 variants is based on their potential functional implication in ITPR3 gene. The rs3748079 SNP, located in promoter region of ITPR3 gene, has been found to upregulate ITPR3 mRNA expression in cells having A allele [14]. Another variant, rs2229634 , is a synonymous SNP situated in exon 20, which might affect mRNA stability and splicing [16].…”