Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 341–349 | Cite as

Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans

  • Nimmisha Govind
  • Ananyo Choudhury
  • Bridget Hodkinson
  • Claudia Ickinger
  • Jacqueline Frost
  • Annette Lee
  • Peter K. Gregersen
  • Richard J. Reynolds
  • S. Louis BridgesJr.
  • Scott Hazelhurst
  • Michèle Ramsay
  • Mohammed Tikly
Research Article

Abstract

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203IRBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10−5). Of the SNPs previously associated with RA in Caucasians, one SNP rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.

Notes

Acknowledgments

This study was made possible by a grant to N Govind from Carnegie Corporation of New York, New York, NY, USA (B8749). The authors would like to acknowledge the Connective Tissue Diseases Fund, University of the Witwatersrand, Johannesburg, South Africa, and the Medical Research Council of South Africa for financial support. SL Bridges Jr acknowledges NIH grant R01 AR057202. A Choudhury acknowledges postdoctoral fellowships from National Research Foundation, South Africa, and SPARC postdoctoral fellowship program, University of the Witwatersrand, for financial support. RJ Reynolds is supported by NIH-K01AR060848. S Hazelhurst and M Ramsay acknowledge financial support from the National Research Foundation, South Africa.

Supplementary material

10020_2014_2001341_MOESM1_ESM.pdf (2.7 mb)
Supplementary material, approximately 2.7 MB.

References

  1. 1.
    MacGregor AJ, et al. (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43:30–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Knight JC. (2013) Genomic modulators of the immune response. Trends Genet. 2013 29:74–83.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Trynka G, et al. (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43:1193–201.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Juran BD, et al. (2012) Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum. Mol. Genet. 21:5209–21.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Beecham AH, et al. (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45:1353–60.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cooper JD, et al. (2012) Seven newly identified loci for autoimmune thyroid disease. Hum. Mol. Genet. 21:5202–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Liu JZ, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 45:670-5.Google Scholar
  8. 8.
    Hinks A, et al. (2013) Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat. Genet. 45:664–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Eyre S, et al. (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44:1336–40.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Begovich AB, et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75:330–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Plenge RM, et al. (2005) Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77:1044–60.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lee HS, et al. (2009) Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum. 60:364–71.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ikari K, et al. (2006) Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford). 45:1345–8.CrossRefGoogle Scholar
  14. 14.
    Tikly M, Govind N, Frost J, Ramsay M. (2010) The PTPN22 R620W polymorphism is not associated with systemic rheumatic diseases in South Africans. Rheumatology (Oxford). 49:820–1.CrossRefGoogle Scholar
  15. 15.
    Ikari K, et al. (2005) Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum. 52:3054–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Kang CP, Lee HS, Ju H, Cho H, Kang C, Bae SC. (2006) A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 54:90–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Suzuki A, et al. (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34:395–402.CrossRefPubMedGoogle Scholar
  18. 18.
    Barton A, et al. (2004) 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. 50:1117–21.CrossRefPubMedGoogle Scholar
  19. 19.
    Burr ML, et al. (2010) PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Ann. Rheum. Dis. 69:666–70.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Caponi L, et al. (2005) A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann. Rheum. Dis. 64:587–93.CrossRefPubMedGoogle Scholar
  21. 21.
    Martinez A, et al. (2005) PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford). 44:1263–6.CrossRefGoogle Scholar
  22. 22.
    Remmers EF, et al. (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357:977–86.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. (2007) Association of STAT4 with rheumatoid arthritis in the Korean population. Mol. Med. 13:455–60.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Martell RW, du Toit ED, Kalla AA, Meyers OL. (1989) Association of rheumatoid arthritis with HLA in three South African populations—whites, blacks and a population of mixed ancestry. S. Afr. Med. J. 76:189–90.PubMedGoogle Scholar
  25. 25.
    Mody GM, Hammond MG, Naidoo PD. (1989) HLA associations with rheumatoid arthritis in African blacks. J. Rheumatol. 16:1326–8.PubMedGoogle Scholar
  26. 26.
    Pile KD, Tikly M, Bell JI, Wordsworth BP. (1992) HLA-DR antigens and rheumatoid arthritis in black South Africans: a study of ethnic groups. Tissue Antigens. 39:138–40.CrossRefPubMedGoogle Scholar
  27. 27.
    Meyer PW, et al. (2011) HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients. Arthritis Res. Ther. 13:R160.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Singwe-Ngandeu M, Finckh A, Bas S, Tiercy JM, Gabay C. (2010) Diagnostic value of anti-cyclic citrullinated peptides and association with HLA-DRB1 shared epitope alleles in African rheumatoid arthritis patients. Arthritis Res. Ther. 12:R36.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Arnett FC, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–24.CrossRefGoogle Scholar
  30. 30.
    Cano P, et al. (2007) Common and well-documented HLA alleles: report of the Ad-Hoc committee of the American Society for Histocompatiblity and Immunogenetics. Hum. Immunol. 68:392–417.CrossRefPubMedGoogle Scholar
  31. 31.
    Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. (2010) Data quality control in genetic case-control association studies. Nat. Protoc. 5:1564–73.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38:904–9.CrossRefPubMedGoogle Scholar
  33. 33.
    May A, et al. (2013) Genetic diversity in black South Africans from Soweto. BMC Genomics. 14:644.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lee HS, et al. (2008) Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus. Mol. Med. 14:293–300.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Raychaudhuri S, et al. (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44:291–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ding B, et al. (2009) Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. Arthritis Rheum. 60:30–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Stahl EA, et al. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42:508–14.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. (2013) Dynamic binding of RBPJ is determined by Notch signaling status. Genes. Dev. 27:1059–71.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Grotenboer NS, Ketelaar ME, Koppelman GH, Nawijn MC. (2013) Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology. J. Allergy Clin. Immunol. 131:856–65.CrossRefPubMedGoogle Scholar
  40. 40.
    Nakki A, et al. (2010) Allelic variants of IL1R1 gene associate with severe hand osteoarthritis. BMC Med. Genet. 11:50.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gardin A, White J. (2011) The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice. Acta Ophthalmol. 89 Suppl s248.Google Scholar
  42. 42.
    Franke A, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42:1118–25.Google Scholar
  43. 43.
    Dehghan A, et al. (2011) Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation. 123:731–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Dehghan A, et al. Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ. Cardiovasc. Genet. 22:125-33.Google Scholar
  45. 45.
    Ellinghaus E, et al. (2010) Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat. Genet. 42:991–5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Huffmeier U, et al. (2010) Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat. Genet. 42:996–9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Chung SA, et al. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS. Genet. 7:e1001323.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hughes LB, et al. (2010) Most common SNPs associated with rheumatoid arthritis in subjects of European ancestry confer risk of rheumatoid arthritis in African-Americans. Arthritis Rheum. 62:3547–53.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Teo YY, Small KS, Kwiatkowski DP. (2010) Methodological challenges of genome-wide association analysis in Africa. Nat. Rev. Genet. 11:149–60.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Beighton P, Solomon L, Valkenburg HA. (1975) Rheumatoid arthritis in a rural South African Negro population. Ann. Rheum. Dis. 34:136–41.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Maritz NG, Gerber AJ, Greyling SJ, Sanda BB. (2003) The rheumatoid wrist in black South African patients. J. Hand Surg. Br. 28:373–5.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Nimmisha Govind
    • 1
  • Ananyo Choudhury
    • 2
  • Bridget Hodkinson
    • 1
  • Claudia Ickinger
    • 1
  • Jacqueline Frost
    • 3
  • Annette Lee
    • 4
  • Peter K. Gregersen
    • 4
  • Richard J. Reynolds
    • 5
  • S. Louis BridgesJr.
    • 5
  • Scott Hazelhurst
    • 2
    • 6
  • Michèle Ramsay
    • 2
    • 3
  • Mohammed Tikly
    • 1
    • 2
  1. 1.Division of Rheumatology, Faculty of Health SciencesChris Hani Baragwanath Academic Hospital, University of the WitwatersrandJohannesburgSouth Africa
  2. 2.Sydney Brenner Institute for Molecular BioscienceUniversity of the WitwatersrandJohannesburgSouth Africa
  3. 3.Division of Human Genetics, National Health Laboratory Service, School of Pathology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
  4. 4.Feinstein Institute for Medical ResearchManhassetUSA
  5. 5.Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamUSA
  6. 6.School of Electrical and Information EngineeringUniversity of the WitwatersrandJohannesburgSouth Africa

Personalised recommendations