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

Ann Rheum Dis. 2015 Mar;74(3):e19. doi: 10.1136/annrheumdis-2013-204581. Epub 2014 Jan 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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