INTRODUCTION: This study investigated five confirmed rheumatoid arthritis (RA) 
susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) 
for association with susceptibility and severity in an inception cohort.
METHODS: The magnitude of association for each genotype was assessed in 1,046 RA 
subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. 
Additional exploratory subanalyses were undertaken in subgroups defined by 
autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or 
disease severity (baseline articular erosions, Health Assessment Questionnaire 
(HAQ) score and swollen joint count (SJC)).
RESULTS: In the total RA inception cohort, the HLA-DRB1 shared epitope 
(per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 
1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 
0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated 
with RA. The magnitude of association for these loci was increased in those 
patients who were autoantibody-positive. PTPN22 was associated with 
autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no 
evidence of association between these five genetic loci and baseline erosions or 
SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was 
significantly associated with baseline HAQ, however, following adjustment for 
symptom duration (P trend = 0.03).
CONCLUSIONS: These findings support the mounting evidence that different genetic 
loci are associated with autoantibody-positive and autoantibody-negative RA, 
possibly suggesting that many of the genes identified to date are associated 
with autoantibody production. Additional studies with a specific focus on 
autoantibody-negative RA will be needed to identify the genes predisposing to 
this RA subgroup. The TRAF1/C5 locus in particular warrants further 
investigation in RA as a potential disease severity locus.