Interaction of PTPN2 and vitamin d gc sequence variants and risk of juvenile idiopathic arthritis in the childhood arthritis risk factor identification study (clarity)

Abstract

Aim: The causes of autoimmune diseases (AIDs), including juvenile idiopathic arthritis (JIA) are presumed to involve the interplay of multiple genes and environment. Vitamin D interacts with genes via vitamin D response elements (VDREs). The gene PTPN2 associated with various AIDs including JIA, carries a VDRE and is regulated by vitamin D. Recently, an interaction between PTPN2 and VDR (vitamin D receptor gene) was reported for type 1 diabetes, such that disease association with VDR differed by PTPN2 genotype.We aimed to detect interaction between PTPN2 and VDR, or with other vitamin D pathway genes (GC, CYP2R1, DHCR7 CYP24A1), for risk of JIA. Methods: 15 SNPs were genotyped in 324 JIA cases and 568 controls from the CLARITY study.We looked for association of each SNP with JIA in the entire dataset, and performed sensitivity analyses restricting to Caucasians (case n = 204, control n = 348) to control for population stratification.We then looked for interaction of PTPN2 with vitamin D genes in determining JIA risk. All analyses were carried out using the PLINK program. Results: No SNPs were individually associated with JIA, except GC rs1155563 which was marginally associated in the entire dataset (p = 0.023), but not in Caucasians. An interaction was observed between PTPN2 andVDR in the entire dataset (OR-int = 1.58, p = 0.016), but not in Caucasians. However, interactions were observed between PTPN2 and GC SNPs which were evident overall and particularly among Caucasians (eg PTPN2 rs254151 and GC rs1155563, OR-int = 11.1, p = 0.00091). Conclusions:We identified potential interaction between PTPN2 and GC in JIA. This is consistent with the notion that PTPN2 is responsive to vitamin D, since GC delivers circulating vitamin D to target cells, and rs1155563 is associated with circulating vitamin D levels. Our data suggests that vitamin D may be an environmental factor that interacts with immunerelated genes in JIA.