The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females.
A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.
Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
R C
RC
Chiaroni-Clarke
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Center for Applied Genomics, Department of Pediatrics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Y R
YR
Li
Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria, Australia.|Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
J E
JE
Munro
Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
R A
RA
Chavez
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia.
K J
KJ
Scurrah
Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
A
A
Pezic
Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria, Australia.|Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
J D
JD
Akikusa
Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria, Australia.|Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
R C
RC
Allen
Department of Paediatric Rheumatology, Monash Children's Hospital, Monash Medical Centre, Clayton, Victoria, Australia.
S E
SE
Piper
Division of Rheumatology and Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, MO, USA.
M L
ML
Becker
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
S D
SD
Thompson
Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.
B A
BA
Lie
Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
B
B
Flato
Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
O
O
Forre
Pediatric Rheumatology, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
M
M
Punaro
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
C
C
Wise
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.|Cancer and Disease Epigenetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
R
http://orcid.org/0000-0002-9510-4181
R
Saffery
Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
T H
TH
Finkel
Center for Applied Genomics, Department of Pediatrics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
H
H
Hakonarson
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.|Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
A-L
AL
Ponsonby
Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
J A
JA
Ellis
D001171:Arthritis, Juvenile / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012737:Sex Factors
C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22