Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene

Steven Gazal¹, Karim Sacre², Yannick Allanore³, Maria Teruel⁴, Alison H Goodall⁵; (The CARDIOGENICS consortium); Shigeto Tohma⁶, Lars Alfredsson⁷, Yukinori Okada⁸, Gang Xie⁹, Arnaud Constantin¹⁰, Alejandro Balsa¹¹, Aya Kawasaki¹², Pascale Nicaise¹³, Christopher Amos¹⁴, Luis Rodriguez-Rodriguez¹⁵, Gilles Chiocchia¹⁶, Catherine Boileau¹⁷, Jinyi Zhang⁹, Olivier Vittecoq¹⁸, Thomas Barnetche¹⁹, Miguel A Gonzalez Gay²⁰, Hiroshi Furukawa⁶, Alain Cantagrel¹⁰, Xavier Le Loët¹⁸, Takayuki Sumida²¹, Margarita Hurtado-Nedelec²², Christophe Richez¹⁹, Sylvie Chollet-Martin¹³, Thierry Schaeverbeke¹⁹, Bernard Combe²³, Liliane Khoryati¹⁹, Baptiste Coustet²⁴, Jammel El-Benna²⁵, Katherine Siminovitch⁹, Robert Plenge²⁶, Leonid Padyukov²⁷, Javier Martin⁴, Naoyuki Tsuchiya¹², Philippe Dieudé²⁸

Affiliations

¹ Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
² Department of Internal Medicine, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, INSERM U699, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
³ 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.
⁴ Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
⁵ 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.
⁶ Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁷ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ 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.
⁹ Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Department of Rheumatology, UMR 1027, INSERM, Toulouse III University, Purpan Hospital, CHU Toulouse, Toulouse, France.
¹¹ Department of Rheumatology, Hospital La Paz, Madrid, Spain.
¹² Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan.
¹³ Department of Immunology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
¹⁴ Genomic Medicine Department of Community, Family Medicine Geisel School of Medicine, Dartmouth College, USA.
¹⁵ Department of Rheumatology, Hospital Clinico, Madrid, Spain.
¹⁶ INSERM U1016, University of Paris Descartes, Cochin Hospital, Paris, France.
¹⁷ INSERM U698, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
¹⁸ Department of Rheumatology, CHU de Rouen-Hopitaux de Rouen and INSERM U905, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy, France.
¹⁹ Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
²⁰ Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
²¹ Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan.
²² 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.
²³ Department of Rheumatology, Montpellier University Hospital, Montpellier, France.
²⁴ Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
²⁵ INSERM U773 CRB3, F-75018, Paris, France.
²⁶ Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA.
²⁷ Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁸ 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.

PMID: 24448344
DOI: 10.1136/annrheumdis-2013-204581

Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene

Steven Gazal et al. Ann Rheum Dis. 2015 Mar.

. 2015 Mar;74(3):e19.

doi: 10.1136/annrheumdis-2013-204581. Epub 2014 Jan 21.

Authors

Affiliations

¹ Plateforme de Génomique Constitutionnelle Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
² Department of Internal Medicine, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, INSERM U699, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
³ 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.
⁴ Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
⁵ 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.
⁶ Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁷ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ 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.
⁹ Samuel Lunenfeld and Toronto General Research Institutes and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Department of Rheumatology, UMR 1027, INSERM, Toulouse III University, Purpan Hospital, CHU Toulouse, Toulouse, France.
¹¹ Department of Rheumatology, Hospital La Paz, Madrid, Spain.
¹² Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan.
¹³ Department of Immunology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
¹⁴ Genomic Medicine Department of Community, Family Medicine Geisel School of Medicine, Dartmouth College, USA.
¹⁵ Department of Rheumatology, Hospital Clinico, Madrid, Spain.
¹⁶ INSERM U1016, University of Paris Descartes, Cochin Hospital, Paris, France.
¹⁷ INSERM U698, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
¹⁸ Department of Rheumatology, CHU de Rouen-Hopitaux de Rouen and INSERM U905, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy, France.
¹⁹ Department of Rheumatology, Pellegrin Hospital, Bordeaux Selagen University, Bordeaux, France.
²⁰ Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
²¹ Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan.
²² 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.
²³ Department of Rheumatology, Montpellier University Hospital, Montpellier, France.
²⁴ Department of Rheumatology, DHU FIRE, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
²⁵ INSERM U773 CRB3, F-75018, Paris, France.
²⁶ Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA.
²⁷ Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁸ 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.

PMID: 24448344
DOI: 10.1136/annrheumdis-2013-204581

Abstract

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.

Keywords: Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene

Affiliations

Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene

Authors

Affiliations

Abstract

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LinkOut - more resources

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