Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Genes Immun. 2011 Oct;12(7):568-74. doi: 10.1038/gene.2011.30. Epub 2011 May 26.


Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Arthritis, Rheumatoid / ethnology
  • Arthritis, Rheumatoid / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Indians, North American / genetics*
  • Male
  • Models, Genetic
  • Neprilysin / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, Tumor Necrosis Factor, Member 14 / genetics
  • TNF Receptor-Associated Factor 1 / genetics


  • HLA-DRB1 Chains
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNF Receptor-Associated Factor 1
  • TNFRSF14 protein, human
  • MMEL1 protein, human
  • Neprilysin