Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis

Justine A. Ellis, Katrina J. Scurrah, Yun R. Li, Anne Louise Ponsonby, Raul A. Chavez, Angela Pezic, Terence Dwyer, Jonathan D. Akikusa, Roger C. Allen, Mara L. Becker, Susan D. Thompson, Benedicte A. Lie, Berit Flatø, Øystein Førre, Marilynn Punaro, Carol Wise, Terri H. Finkel, Hakon Hakonarson, Jane E. Munro

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)113-120
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
StatePublished - Jan 2015


  • Autoimmune disease
  • Complex disease
  • Epistasis
  • Juvenile idiopathic arthritis
  • Vitamin D
  • Vitamin D
  • binding protein

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology


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