Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers
- Darren Plant1,
- Edward Flynn1,
- Hamdi Mbarek2,
- Philippe Dieudé2,
- François Cornelis2,
- Lisbeth Ärlestig3,
- Solbritt Rantapää Dahlqvist3,
- George Goulielmos4,
- Dimitrios T Boumpas4,
- Prodromos Sidiropoulos4,
- Julia S Johansen5,
- Lykke M Ørnbjerg5,
- Merete Lund Hetland5,
- Lars Klareskog6,
- Andrew Filer7,8,
- Christopher D Buckley7,8,
- Karim Raza7,8,
- Torsten Witte9,
- Reinhold E Schmidt9,
- Jane Worthington1
- 1arc-Epidemiology Unit, University of Manchester, Manchester, UK
- 2Department of Rheumatology, Evry University, Paris, France
- 3Department of Rheumatology, University Hospital, Umeå, Sweden
- 4Clinic of Rheumatology, Department of Medicine, University of Crete, Heraklion, Greece
- 5DANBIO, Copenhagen University Hospital at Hvidovre, Copenhagen, Denmark
- 6Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- 7Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
- 8Rheumatology Research Group, The University of Birmingham, Birmingham, UK
- 9Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
- Correspondence to Dr Darren Plant, arc-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester M13 9PT, UK;
- Accepted 31 January 2010
- Published Online First 24 May 2010
Background Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50–60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk.
Objectives To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results.
Methods 3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data.
Results After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers.
Conclusions In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained.
Funding Provided by the European Community's Sixth Framework Programme AutoCure and by the Wellcome Trust under award 085475.
Competing interests None.
Ethics approval This study was conducted with the approval of each individual centre.
Provenance and peer review Not commissioned; externally peer reviewed.
This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl