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A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis
  1. Leonid Padyukov1,
  2. Mark Seielstad2,3,
  3. Rick T H Ong2,
  4. Bo Ding4,
  5. Johan Rönnelid5,
  6. Maria Seddighzadeh1,
  7. Lars Alfredsson4,
  8. Lars Klareskog1,
  9. the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) Study Group
  1. 1Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2The Genome Institute of Singapore, Singapore
  3. 3The Institute for Human Genetics and Department of Laboratory Medicine, University of California, San Francisco School of Medicine, San Francisco, California, USA
  4. 4The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  5. 5The Unit for Clinical Immunology, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Seielstad, at the Genome Institute of Singapore, 60 Biopolis St, Singapore 138672; seielstadm{at}gis.a-star.edu.sg

Abstract

Background Rheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies (GWAS) have only been published from ACPA-positive subsets of RA or from studies that have not separated the two subsets. The aim of the current study is to provide and compare GWAS data for both subsets.

Methods and results GWAS using the Illumina 300K chip was performed for 774 ACPA-negative patients with RA, 1147 ACPA-positive patients with RA and 1079 controls from the Swedish population-based case–control study EIRA. Imputation was performed which allowed comparisons using 1 723 056 single nucleotide polymorphisms (SNPs). No SNP achieved genome-wide significance (2.9 × 10–8) in the comparison between ACPA-negative RA and controls. A case–case association study was then performed between ACPA-negative and ACPA-positive RA groups. The major difference in this analysis was in the HLA region where 768 HLA SNPs passed the threshold for genome-wide significance whereas additional contrasting SNPs did not reach genome-wide significance. However, one SNP close to the RPS12P4 locus in chromosome 2 reached a p value of 2 × 106 and this locus can thus be considered as a tentative candidate locus for ACPA-negative RA.

Conclusions ACPA-positive and ACPA-negative RA display significant risk allele frequency differences which are mainly confined to the HLA region. The data provide further support for distinct genetic aetiologies of RA subsets and emphasise the need to consider them separately in genetic as well as functional studies of this disease.

This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl

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Footnotes

  • LP and MS contributed equally to this work.

  • Competing interests None.

  • Funding Supported by grants from the Swedish Research Council, the Swedish Council for Working Life and Social Research, King Gustaf V's 80-year Foundation, the Swedish Rheumatism Foundation, the insurer, AFA and the EU-supported projects AutoCure and Masterswitch. The Agency for Science Technology and Research (ASTAR), Singapore supported the genotyping and data analysis. The funding agencies had no influence on study design, evaluation of results and decision to publish the data.

  • Ethics approval This study was conducted with the approval of the Regional Ethical Review Board in Stockholm.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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