Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers

Abstract

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.

Figure 1

Meta-analysis of previously published data, together with data generated in this study (labelled: UK_rep2 (UK), Greece, France, Germany and EIRA for Scandinavian cohorts) for the single-nucleotide polymorphism maker rs2476601 (PTPN22). Odds ratio (OR) point estimate and 95% CI (horizontal line) for each cohort are shown. The diamond represents the meta-analysis point estimate and CI. The scale of the effect size is given on the x-axis. EIRA, Epidemiological Investigation of Rheumatoid Arthritis; WTCCC, Wellcome Trust Case Control Consortium.