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

Genes & Immunity volume 12, pages 568–574 (2011)Cite this article

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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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References

  1. Silman AJ, Pearson JE . Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 2002; 4 (Suppl 3): S265–S272.

    Article  Google Scholar 

  2. Boyer GS, Templin DW, Lanier AP . Rheumatic diseases in Alaskan Indians of the southeast coast: high prevalence of rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 1991; 18: 1477–1484.

    CAS  PubMed  Google Scholar 

  3. Ferucci ED, Schumacher MC, Lanier AP, Murtaugh MA, Edwards S, Helzer LJ et al. Arthritis prevalence and associations in American Indian and Alaska Native people. Arthritis Rheum 2008; 59: 1128–1136.

    Article  Google Scholar 

  4. Peschken CA, Esdaile JM . Rheumatic diseases in North America's indigenous peoples. Semin Arthritis Rheum 1999; 28: 368–391.

    Article  CAS  Google Scholar 

  5. Holoshitz J . The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol 2010; 22: 293–298.

    Article  CAS  Google Scholar 

  6. Williams RC, Jacobsson LT, Knowler WC, del PA, Kostyu D, McAuley JE et al. Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis. Hum Immunol 1995; 42: 90–94.

    Article  CAS  Google Scholar 

  7. Oen K, El-Gabalawy HS, Canvin JM, Hitchon C, Chalmers IM, Schroeder M et al. HLA associations of seropositive rheumatoid arthritis in a Cree and Ojibway population. J Rheumatol 1998; 25: 2319–2323.

    CAS  PubMed  Google Scholar 

  8. El-Gabalawy HS, Robinson DB, Hart D, Elias B, Markland J, Peschken CA et al. Immunogenetic risks of anti-cyclical citrullinated peptide antibodies in a North American Native population with rheumatoid arthritis and their first-degree relatives. J Rheumatol 2009; 36: 1130–1135.

    Article  CAS  Google Scholar 

  9. Nelson JL, Boyer G, Templin D, Lanier A, Barrington R, Nisperos B et al. HLA antigens in Tlingit Indians with rheumatoid arthritis. Tissue Antigens 1992; 40: 57–63.

    Article  CAS  Google Scholar 

  10. Templin DW, Boyer GS, Lanier AP, Nelson JL, Barrington RA, Hansen JA et al. Rheumatoid arthritis in Tlingit Indians: clinical characterization and HLA associations. J Rheumatol 1994; 21: 1238–1244.

    CAS  PubMed  Google Scholar 

  11. Ferucci ED, Templin DW, Lanier AP . Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature. Semin Arthritis Rheum 2005; 34: 662–667.

    Article  Google Scholar 

  12. Deighton CM, Walker DJ, Griffiths ID, Roberts DF . The contribution of HLA to rheumatoid arthritis. Clin Genet 1989; 36: 178–182.

    Article  CAS  Google Scholar 

  13. Li Y, Begovich AB . Unraveling the genetics of complex diseases: susceptibility genes for rheumatoid arthritis and psoriasis. Semin Immunol 2009; 21: 318–327.

    Article  CAS  Google Scholar 

  14. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008; 40: 1216–1223.

    Article  CAS  Google Scholar 

  15. Lee HS, Korman BD, Le JM, Kastner DL, Remmers EF, Gregersen PK et al. Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum 2009; 60: 364–371.

    Article  CAS  Google Scholar 

  16. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K . Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 2005; 50: 264–266.

    Article  Google Scholar 

  17. Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M, Yamanaka H et al. Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford) 2006; 45: 1345–1348.

    Article  CAS  Google Scholar 

  18. Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S et al. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004; 50: 1117–1121.

    Article  CAS  Google Scholar 

  19. Burr ML, Naseem H, Hinks A, Eyre S, Gibbons LJ, Bowes J et al. PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Ann Rheum Dis 2010; 69: 666–670.

    Article  CAS  Google Scholar 

  20. Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F et al. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 2005; 64: 587–593.

    Article  CAS  Google Scholar 

  21. Barnabe C, Elias B, Bartlett J, Roos L, Peschken C . Arthritis in aboriginal Manitobans: evidence for a high burden of disease. J Rheumatol 2008; 35: 1145–1150.

    PubMed  Google Scholar 

  22. Ioan-Facsinay A, Willemze A, Robinson DB, Peschken CA, Markland J, van der Woude D et al. Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease. Arthritis Rheum 2008; 58: 3000–3008.

    Article  Google Scholar 

  23. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, yre S, Thomson BP et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010; 42: 508–514.

    Article  CAS  Google Scholar 

  24. Perdigones N, Vigo AG, Lamas JR, Martinez A, Balsa A, Pascual-Salcedo D et al. Evidence of epistasis between TNFRSF14 and TNFRSF6B polymorphisms in patients with rheumatoid arthritis. Arthritis Rheum 2010; 62: 705–710.

    Article  CAS  Google Scholar 

  25. Cheung TC, Oborne LM, Steinberg MW, Macauley MG, Fukuyama S, Sanjo H et al. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. J Immunol 2009; 183: 7286–7296.

    Article  CAS  Google Scholar 

  26. Kang YM, Kim SY, Kang JH, Han SW, Nam EJ, Kyung HS et al. LIGHT up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytes. Arthritis Rheum 2007; 56: 1106–1117.

    Article  CAS  Google Scholar 

  27. Pierer M, Brentano F, Rethage J, Wagner U, Hantzschel H, Gay RE et al. The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 1063–1070.

    Article  CAS  Google Scholar 

  28. Steinberg MW, Shui JW, Ware CF, Kronenberg M . Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners. Semin Immunopathol 2009; 31: 207–221.

    Article  CAS  Google Scholar 

  29. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 2007; 357: 1199–1209.

    Article  CAS  Google Scholar 

  30. Cordell HJ . Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet 2009; 10: 392–404.

    Article  CAS  Google Scholar 

  31. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E . Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 2003; 171: 538–541.

    Article  CAS  Google Scholar 

  32. Hill JA, Bell DA, Brintnell W, Yue D, Wehrli B, Jevnikar AM et al. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med 2008; 205: 967–979.

    Article  CAS  Google Scholar 

  33. Oen K, Robinson DB, Nickerson P, Katz SJ, Cheang M, Peschken CA et al. Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes. J Rheumatol 2005; 32: 983–991.

    CAS  PubMed  Google Scholar 

  34. Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 2007; 80: 867–875.

    Article  Google Scholar 

  35. Cordell HJ . Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet 2002; 11: 2463–2468.

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

    H S El-Gabalawy, D B Robinson, K G Oen, I Smolik, B Elias, D Hart & C N Bernstein

  2. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    N A Daha & J J Houwing-Duistermaat

  3. Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Y Sun, Y Lu & K A Siminovitch

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  1. H S El-Gabalawy
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Correspondence to H S El-Gabalawy.

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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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