Identification of Secreted Phosphoprotein 1 Gene as a new Rheumatoid Arthritis Susceptibility Gene
Steven Gazal
(1)
,
Karim Sacre
(2)
,
Yannick Allanore
(3, 4)
,
Maria Teruel
(5)
,
Alison H Goodall
(6)
,
Shigeto Tohma
(7)
,
Lars Alfredsson
(8)
,
Yukinori Okada
(9)
,
Gang Xie
(10)
,
Arnaud Constantin
(11)
,
Alejandro Balsa
(12)
,
Aya Kawasaki
(7)
,
Pascale Nicaise
(13)
,
Christopher Amos
(14)
,
Luis Rodriguez-Rodriguez
(15)
,
Gilles Chioccia
(4)
,
Catherine Boileau
(16)
,
Jinyi Zhang
(10)
,
Olivier Vittecoq
(17)
,
Thomas Barnetche
(18)
,
Miguel A. Gonzalez Gay
(19)
,
Hiroshi Furukawa
(7)
,
Alain Cantagrel
(11)
,
Xavier Le Loët
(17)
,
Takayuki Sumida
(7)
,
Margarita Hurtado-Nedelec
(20, 21)
,
Christophe Richez
(18)
,
Sylvie Chollet-Martin
(13)
,
Thierry Schaeverbeke
(18)
,
Bernard Combe
(22)
,
Liliane Khoryati
(18)
,
Baptiste Coustet
(23)
,
Katherine Siminovitch
(10)
,
Robert Plenge
(24)
,
Leonid Padyukov
(25)
,
Javier Martin
(5)
,
Naoyuki Tsuchiya
(7)
,
Philippe Dieudé
(2, 23)
1
Plateforme de Génomique Constitutionnelle
2 Immunopathologie rénale, récepteurs et inflammation
3 Service de rhumatologie [CHU Cochin]
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 CSIC - Consejo Superior de Investigaciones Cientificas [España] = Spanish National Research Council [Spain]
6 University of Leicester
7 Université de Tsukuba = University of Tsukuba
8 Institute of Environmental Medicine
9 BROAD INSTITUTE - Broad Institute of MIT and Harvard
10 University of Toronto
11 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
12 University Hospital La Paz, Madrid
13 Service d'Immunologie
14 Dartmouth College [Hanover]
15 Rheumatology Service
16 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
17 Service de Rhumatologie [CHU Rouen]
18 Hôpital Pellegrin
19 Hospital Marques de Valdecillas
20 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
21 Service d'hématologie et immunologie
22 IGMM - Institut de Génétique Moléculaire de Montpellier
23 Service de Rhumatologie
24 Merck & Co. Inc - Merck Sharp and Dohme
25 Rheumatology Unit, Department of Medicine
2 Immunopathologie rénale, récepteurs et inflammation
3 Service de rhumatologie [CHU Cochin]
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 CSIC - Consejo Superior de Investigaciones Cientificas [España] = Spanish National Research Council [Spain]
6 University of Leicester
7 Université de Tsukuba = University of Tsukuba
8 Institute of Environmental Medicine
9 BROAD INSTITUTE - Broad Institute of MIT and Harvard
10 University of Toronto
11 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
12 University Hospital La Paz, Madrid
13 Service d'Immunologie
14 Dartmouth College [Hanover]
15 Rheumatology Service
16 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
17 Service de Rhumatologie [CHU Rouen]
18 Hôpital Pellegrin
19 Hospital Marques de Valdecillas
20 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
21 Service d'hématologie et immunologie
22 IGMM - Institut de Génétique Moléculaire de Montpellier
23 Service de Rhumatologie
24 Merck & Co. Inc - Merck Sharp and Dohme
25 Rheumatology Unit, Department of Medicine
Karim Sacre
- Fonction : Auteur
- PersonId : 770565
- ORCID : 0000-0002-6544-234X
Yannick Allanore
- Fonction : Auteur
- PersonId : 926007
Arnaud Constantin
- Fonction : Auteur
- PersonId : 1290743
- ORCID : 0000-0003-2618-2888
Catherine Boileau
- Fonction : Auteur
- PersonId : 755735
- ORCID : 0000-0002-0371-7539
- IdRef : 057319952
Margarita Hurtado-Nedelec
- Fonction : Auteur
- PersonId : 772712
- ORCID : 0000-0001-9681-7653
- IdRef : 204500508
Christophe Richez
- Fonction : Auteur
- PersonId : 756184
- ORCID : 0000-0002-3029-8739
- IdRef : 114661057
Thierry Schaeverbeke
- Fonction : Auteur
- PersonId : 756185
- ORCID : 0000-0002-6976-643X
Bernard Combe
- Fonction : Auteur
- PersonId : 759313
- ORCID : 0000-0003-4002-1861
Résumé
Objective To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the RA genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals. Methods We analyzed a total of 11,715 RA cases and 26,493 controls from 9 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 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 = 1.29x10-5, ORACPA-negative 1.257 1.135–1.394) and less with ACPA positivity (P = 0.0148, ORACPA-positive 1.072 1.014–1.134]). The odds ratios between these subgroups (i.e., ACPA-positive and -negative) significantly differed (P = 7.33x10-3). 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). Conclusion We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association greater in patients negative for ACPAs.