PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus.
OBJECTIVE
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA.


METHODS
A total of 15 single nucleotide polymorphisms were selected (PImmunochip <1×10(-4)) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity.


RESULTS
We found genome-wide significant association to rs2476601, mapping to PTPN22 (p=1.49×10(-9), OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2×10(-4)). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27×10(-9)).


CONCLUSIONS
For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis.
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
John
J
Bowes
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Sabine
S
Loehr
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Ashley
A
Budu-Aggrey
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Steffen
S
Uebe
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester, UK.
Ian N
IN
Bruce
Monash University, Melbourne, Victoria, Australia.
Marie
M
Feletar
NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Helena
H
Marzo-Ortega
NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Philip
P
Helliwell
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
Anthony W
AW
Ryan
Adelaide and Meath Hospital and Trinity College Dublin, Dublin, Ireland.
David
D
Kane
Royal National Hospital for Rheumatic Diseases and Department Pharmacy and Pharmacology, University of Bath, Bath, UK.
Eleanor
E
Korendowych
Department of Public Health and Clinical Medicine, Rheumatology, University Hospital, Umeå, Sweden.
Gerd-Marie
GM
Alenius
Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome 'Tor Vergata' and Fondazione PTV 'Policlinico Tor Vergata', Rome, Italy.
Emiliano
E
Giardina
Rheumatology Department, Haywood Hospital, Health Services Research Unit, Institute of Science and Technology in Medicine, Keele University.
Jonathan
J
Packham
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
Ross
R
McManus
Department of Rheumatology, St. Vincent's University Hospital, UCD School of Medicine and Medical Sciences and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Oliver
O
FitzGerald
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
Matthew A
MA
Brown
Division of Rheumatology and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University, Frankfurt, Germany.
Frank
F
Behrens
Division of Rheumatology and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University, Frankfurt, Germany.
Harald
H
Burkhardt
Royal National Hospital for Rheumatic Diseases and Department Pharmacy and Pharmacology, University of Bath, Bath, UK.
Neil
N
McHugh
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Ulrike
U
Huffmeier
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester, UK.
Pauline
P
Ho
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Andre
A
Reis
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester, UK.
Anne
A
Barton
D015535:Arthritis, Psoriatic / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics; D012307:Risk Factors
C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22