title: Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis.
abstract: 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.
authors.affiliation: Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address: justine.ellis@mcri.edu.au.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Scurrah
authors.affiliation: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics and Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia,PA 19104, USA.
authors.forename: Yun R
authors.initials: YR
authors.lastname: Li
authors.affiliation: Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia; Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Ponsonby
authors.affiliation: Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Chavez
authors.affiliation: Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Pezic
authors.affiliation: Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.affiliation: Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Akikusa
authors.affiliation: Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Allen
authors.affiliation: Divisions of Rheumatology and Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Becker
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Department of Immunology, Oslo University Hospital and University of Oslo, Rikshospitalet, 0027 Oslo, Norway.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Flatø
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway.
authors.forename: Oystein
authors.initials: O
authors.lastname: Førre
authors.affiliation: Pediatric Rheumatology, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.affiliation: Department of Pediatrics, Nemours Children's Hospital, Orlando, FL 32827, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Finkel
authors.affiliation: Center for Applied Genomics and Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia,PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Munro
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014807:Vitamin D / Q000378:metabolism*; D014809:Vitamin D-Binding Protein / Q000378:metabolism
chemical_list: D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
keywords: Autoimmune disease; Complex disease; Epistasis; Juvenile idiopathic arthritis; Vitamin D; Vitamin D binding protein