Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting 
both joints and extra-articular tissues. Although some genetic risk factors for 
RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not 
fully account for the observed heritability. To identify additional 
susceptibility loci, we carried out a multi-tiered, case-control association 
study, genotyping 25,966 putative functional SNPs in 475 white North American RA 
patients and 475 matched controls. Significant markers were genotyped in two 
additional, independent, white case-control sample sets (661 cases/1322 controls 
from North America and 596 cases/705 controls from The Netherlands) identifying 
a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA 
(OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive 
fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb 
region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a 
staged-approach. Significant single marker results (P(comb)<0.01) spanned a 
large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified 
SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 
into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the 
most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed 
association patterns for these SNPs had heightened statistical significance and 
a higher degree of consistency across sample sets. In addition, the allele 
frequencies for these SNPs displayed reduced variability between control groups 
when compared to other SNPs. Lastly, in combination with the other two known 
genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate 
more than a 45-fold RA-risk differential.