TY - JOUR
T1 - Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis
AU - Ellis, Justine A.
AU - Scurrah, Katrina J.
AU - Li, Yun R.
AU - Ponsonby, Anne Louise
AU - Chavez, Raul A.
AU - Pezic, Angela
AU - Dwyer, Terence
AU - Akikusa, Jonathan D.
AU - Allen, Roger C.
AU - Becker, Mara L.
AU - Thompson, Susan D.
AU - Lie, Benedicte A.
AU - Flatø, Berit
AU - Førre, Øystein
AU - Punaro, Marilynn
AU - Wise, Carol
AU - Finkel, Terri H.
AU - Hakonarson, Hakon
AU - Munro, Jane E.
N1 - Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2015/1
Y1 - 2015/1
N2 - Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint = 0.45, p = 0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6 × 10-9 to 7.5 × 10-7). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.
AB - Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint = 0.45, p = 0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6 × 10-9 to 7.5 × 10-7). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.
KW - Autoimmune disease
KW - Complex disease
KW - Epistasis
KW - Juvenile idiopathic arthritis
KW - Vitamin D
KW - Vitamin D
KW - binding protein
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U2 - 10.1016/j.jsbmb.2014.10.012
DO - 10.1016/j.jsbmb.2014.10.012
M3 - Article
C2 - 25460303
AN - SCOPUS:84988246907
SN - 0960-0760
VL - 145
SP - 113
EP - 120
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
ER -