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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 
Abstract : 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.
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Submitted on : Monday, November 24, 2014 - 3:01:52 PM
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Steven Gazal, Karim Sacre, yannick Allanore, Maria Teruel, Alison H Goodall, et al.. Identification of Secreted Phosphoprotein 1 Gene as a new Rheumatoid Arthritis Susceptibility Gene. Annals of the Rheumatic Diseases, BMJ Publishing Group, 2014, [Epub ahead of print]. ⟨10.1136/annrheumdis-2013-204581⟩. ⟨inserm-01086600⟩



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