Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.
OBJECTIVE
To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA).


METHODS
Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays.


RESULTS
The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79).


CONCLUSIONS
Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
A
A
Serrano
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
A
A
Márquez
NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK.
S L
SL
Mackie
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
F D
FD
Carmona
Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.
R
R
Solans
Department of Rheumatology, Hospital Xeral-Calde, Lugo, Spain.
J A
JA
Miranda-Filloy
Vasculitis Research Unit, Department of Autoimmune and Systemic Diseases, Hospital Clinic, University of Barcelona, Centre de Recerca Biomèdica Cellex (IDIBAPS), Barcelona, Spain.
J
J
Hernández-Rodríguez
Vasculitis Research Unit, Department of Autoimmune and Systemic Diseases, Hospital Clinic, University of Barcelona, Centre de Recerca Biomèdica Cellex (IDIBAPS), Barcelona, Spain.
M C
MC
Cid
Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid, Spain.
S
S
Castañeda
Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain.
I C
IC
Morado
Department of Rheumatology, Hospital Universitario de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
J
J
Narváez
Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain.
R
R
Blanco
Department of Internal Medicine, Complejo Hospitalario Universitario de Vigo, Spain.
B
B
Sopeña
Department of Rheumatology, Hospital Ramón y Cajal, Madrid, Spain.
M J
MJ
García-Villanueva
Department of Rheumatology, Grup de recerca cellular en inflamació i cartílag. IMIM (Institut de Recerca Hospital del Mar), Barcelona, Spain.
J
J
Monfort
Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain.
N
N
Ortego-Centeno
Department of Internal Medicine, Hospital de Galdakano, Vizcaya, Spain.
A
A
Unzurrunzaga
Department of Internal Medicine, Corporació Sanitaria Parc Taulí, Instituto Universitario Parc Taulí, UAB, Sabadell, Barcelona, Spain.
B
B
Marí-Alfonso
Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid.
J
J
Sánchez Martín
Department of Rheumatology, Hospital Universitario de La Paz, Madrid, Spain.
E
E
de Miguel
Department of Rheumatology, Hospital Clínico Universitario San Cecilio, Granada.
C
C
Magro
Department of Rheumatology, Hospital Clínico Universitario San Cecilio, Granada.
E
E
Raya
Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany.
N
N
Braun
Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany.
J
J
Latus
Department of Rheumatology, Oslo University Hospital, Oslo, Norway and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
O
O
Molberg
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.
B A
BA
Lie
Department of Clinical Immunology and Rheumatology, University of Luebeck, Bad Bramstedt, Germany.
F
F
Moosig
Hannover Medical School, Hannover, Germany.
T
T
Witte
NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK.
A W
AW
Morgan
Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain.
M A
MA
González-Gay
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
J
J
Martín
D000081247:CSK Tyrosine-Protein Kinase; D016022:Case-Control Studies; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D013700:Giant Cell Arteritis / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D019061:src-Family Kinases / Q000235:genetics*
D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
Gene Polymorphism; Giant Cell Arteritis; Polymyalgia Rheumatica