Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene.
OBJECTIVE
To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the rheumatoid arthritis (RA) genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals.


METHODS
We analysed a total of 11,715 RA cases and 26,493 controls from nine independent cohorts; all individuals were genotyped or had imputed genotypes for SPP1 rs11439060 and rs9138. The effect of the SPP1 rs11439060 and rs9138 risk-allele combination on osteopontin (OPN) expression in macrophages and OPN serum levels was investigated.


RESULTS
We provide evidence for a distinct contribution of SPP1 to RA susceptibility according to ACPA status: the combination of ≥3 SPP1 rs11439060 and rs9138 common alleles was associated mainly with ACPA negativity (p=1.29×10(-5), ORACPA-negative 1.257 (1.135 to 1.394)) and less with ACPA positivity (p=0.0148, ORACPA-positive 1.072 (1.014 to 1.134)). The ORs between these subgroups (ie, ACPA-positive and ACPA-negative) significantly differed (p=7.33×10(-3)). Expression quantitative trait locus analysis revealed an association of the SPP1 risk-allele combination with decreased SPP1 expression in peripheral macrophages from 599 individuals. To corroborate these findings, we found an association of the SPP1 risk-allele combination and low serum level of secreted OPN (p=0.0157), as well as serum level of secreted OPN correlated positively with ACPA production (p=0.005; r=0.483).


CONCLUSIONS
We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association being greater in patients negative for ACPAs.
Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Steven
S
Gazal
Department of Internal Medicine, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, INSERM U699, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Karim
K
Sacre
Department A of Rheumatology, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris Descartes Paris, France INSERM U1016, University of Paris Descartes, Cochin Hospital, Paris, France.
Yannick
Y
Allanore
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
Maria
M
Teruel
Department of Cardiovascular Sciences, University of Leicester & Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.
Alison H
AH
Goodall
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Shigeto
S
Tohma
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Lars
L
Alfredsson
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
Yukinori
Y
Okada
Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Gang
G
Xie
Department of Rheumatology, UMR 1027, INSERM, Toulouse III University, Purpan Hospital, CHU Toulouse, Toulouse, France.
Arnaud
A
Constantin
Department of Rheumatology, Hospital La Paz, Madrid, Spain.
Alejandro
A
Balsa
Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan.
Aya
A
Kawasaki
Department of Immunology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Pascale
P
Nicaise
Genomic Medicine Department of Community, Family Medicine Geisel School of Medicine, Dartmouth College, USA.
Christopher
C
Amos
Department of Rheumatology, Hospital Clinico, Madrid, Spain.
Luis
L
Rodriguez-Rodriguez
INSERM U1016, University of Paris Descartes, Cochin Hospital, Paris, France.
Gilles
G
Chiocchia
INSERM U698, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Catherine
C
Boileau
Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jinyi
J
Zhang
Department of Rheumatology, CHU de Rouen-Hopitaux de Rouen and INSERM U905, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy, France.
Olivier
O
Vittecoq
Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
Thomas
T
Barnetche
Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
Miguel A
MA
Gonzalez Gay
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Hiroshi
H
Furukawa
Department of Rheumatology, UMR 1027, INSERM, Toulouse III University, Purpan Hospital, CHU Toulouse, Toulouse, France.
Alain
A
Cantagrel
Department of Rheumatology, CHU de Rouen-Hopitaux de Rouen and INSERM U905, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy, France.
Xavier
X
Le Loët
Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan.
Takayuki
T
Sumida
INSERM U773 CRB3, F-75018, Paris, France Department of Hematology and Immunology, UF Dysfonctionnements Immunitaires Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Margarita
M
Hurtado-Nedelec
Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
Christophe
C
Richez
Department of Immunology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Sylvie
S
Chollet-Martin
Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
Thierry
T
Schaeverbeke
Department of Rheumatology, Montpellier University Hospital, Montpellier, France.
Bernard
B
Combe
Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
Liliane
L
Khoryati
Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Baptiste
B
Coustet
INSERM U773 CRB3, F-75018, Paris, France.
Jammel
J
El-Benna
Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Katherine
K
Siminovitch
Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA.
Robert
R
Plenge
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Leonid
L
Padyukov
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
Javier
J
Martin
Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan.
Naoyuki
http://orcid.org/0000-0002-6776-5580
N
Tsuchiya
Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France Bichat Faculty of Medicine, INSERM U699, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Philippe
P
Dieudé
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide
D001323:Autoantibodies; D010455:Peptides; C506895:SPP1 protein, human; D053495:Osteopontin; D002956:Citrulline
Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis