Abstract
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.
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Acknowledgements
The authors wish to acknowledge the Assembly of Manitoba Chiefs, and the Chiefs and Band Councils of the Norway House and St Theresa Point communities for their support of the research program. Dr El-Gabalawy is supported by Canadian Institutes of Health Research grant, MOP 7770. Dr Siminovitch was supported by Canadian Institutes of Health Research grants, MOP 79321 and IIN-84042, Ontario Research Fund RE01061, Sherman Family Chair in Genomic Medicine, and a Canada Research Chair.
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El-Gabalawy, H., Robinson, D., Daha, N. et al. Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population. Genes Immun 12, 568–574 (2011). https://doi.org/10.1038/gene.2011.30
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DOI: https://doi.org/10.1038/gene.2011.30
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