A genome-wide association study identifies SLC8A3 as a susceptibility locus for ACPA-positive rheumatoid arthritis

Rheumatology (Oxford). 2016 Jun;55(6):1106-11. doi: 10.1093/rheumatology/kew035. Epub 2016 Mar 15.


Objective: RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach.

Methods: A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry.

Results: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)].

Conclusions: SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.

Keywords: anti-citrullinated protein antibodies; genetic risk; genome-wide association study; joint erosions; rheumatoid arthritis.

MeSH terms

  • Adult
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Case-Control Studies
  • Female
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Sodium-Calcium Exchanger / blood
  • Sodium-Calcium Exchanger / genetics*
  • White People / genetics


  • Autoantibodies
  • Peptides, Cyclic
  • SLC38A3 protein, human
  • Sodium-Calcium Exchanger
  • cyclic citrullinated peptide