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

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.

• Authors: Steven Gazal, Karim Sacre, Yannick Allanore, Maria Teruel, Alison H Goodall, (The CARDIOGENICS consortium), Shigeto Tohma, Lars Alfredsson, Yukinori Okada, Gang Xie, Arnaud Constantin, Alejandro Balsa, Aya Kawasaki, Pascale Nicaise, Christopher Amos, Luis Rodriguez-Rodriguez, Gilles Chiocchia, Catherine Boileau, Jinyi Zhang, Olivier Vittecoq, Thomas Barnetche, Miguel A Gonzalez Gay, Hiroshi Furukawa, Alain Cantagrel, Xavier Le Loët, Takayuki Sumida, Margarita Hurtado-Nedelec, Christophe Richez, Sylvie Chollet-Martin, Thierry Schaeverbeke, Bernard Combe, Liliane Khoryati, Baptiste Coustet, Jammel El-Benna, Katherine Siminovitch, Robert Plenge, Leonid Padyukov, Javier Martin, Naoyuki Tsuchiya, Philippe Dieudé
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 74 Issue 3 Pg. e19 (Mar 2015) ISSN: 1468-2060 [Electronic] England
• PMID: 24448344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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.

Chemical References

• Autoantibodies
• Peptides
• SPP1 protein, human
• Osteopontin
• Citrulline

Topics

• Alleles
• Arthritis, Rheumatoid (genetics, immunology)
• Autoantibodies (immunology)
• Case-Control Studies
• Citrulline (immunology)
• Female
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Macrophages (metabolism)
• Male
• Osteopontin (genetics, metabolism)
• Peptides (immunology)
• Polymorphism, Single Nucleotide