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Molecular Medicine

, Volume 23, Issue 1, pp 177–187 | Cite as

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

  • Maria I. Danila
  • Vincent A. Laufer
  • Richard J. Reynolds
  • Qi Yan
  • Nianjun Liu
  • Peter K. Gregersen
  • Annette Lee
  • Marlena Kern
  • Carl D. Langefeld
  • Donna K. Arnett
  • S. Louis BridgesJr.
Research Article

Abstract

More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody-positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10−15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10−4 < p < 3.1 × 10−6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 — but no variants within the major histocompatibility complex — were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

Notes

Acknowledgments

We thank the CLEAR investigators for recruiting participants with rheumatoid arthritis and healthy controls: Doyt Conn, MD (Grady Hospital and Emory University, Atlanta, Georgia); Beth Jonas, MD; Leigh Callahan, PhD (University of North Carolina, Chapel Hill); Edwin Smith, MD (Medical University of South Carolina, Charleston); Richard Brasington, MD (Washington University, St. Louis, Missouri); and Larry W Moreland, MD (University of Pittsburgh). We thank Drs. Robert Kimberly and Jeffrey Edberg for providing data on healthy controls from the Birmingham, Alabama, area. We would also like to thank Gleb Kichaev (David Geffen School of Medicine, University of California, Los Angeles) for helpful discussions regarding trans-ethnic fine mapping.

Supplementary material

10020_2017_2301177_MOESM1_ESM.pdf (1 mb)
Supplementary material, approximately 1.04 MB.

References

  1. 1.
    McInnes IB, Schett G. (2011) The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365: 2205–19.CrossRefGoogle Scholar
  2. 2.
    Nielen MM, et al. (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50:380–6.CrossRefGoogle Scholar
  3. 3.
    Mewar D, et al. (2006) Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis. Arthritis Res. Ther. 8:R128.CrossRefGoogle Scholar
  4. 4.
    Eyre S, et al. (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genet. 44:1336–40.CrossRefGoogle Scholar
  5. 5.
    Danila MI, et al. (2015) The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis. Genes Immun. 16:446–51.CrossRefGoogle Scholar
  6. 6.
    Govind N, et al. (2014) Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans. Mol. Med. 20:341–9.CrossRefGoogle Scholar
  7. 7.
    Yang SK, et al. (2015) Immunochip analysis identification of 6 additional susceptibility loci for Crohn’s disease in Koreans. Inflamm. Bowel Dis. 21:1–7.CrossRefGoogle Scholar
  8. 8.
    Isobe N, et al. (2015) An ImmunoChip study of multiple sclerosis risk in African Americans. Brain. 138(Pt 6):1518–30.CrossRefGoogle Scholar
  9. 9.
    Ramos PS, Shedlock AM, Langefeld CD. (2015) Genetics of autoimmune diseases: insights from population genetics. J. Hum. Genet. 60:657–64.CrossRefGoogle Scholar
  10. 10.
    Okada Y, et al. (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 506:376–81.CrossRefGoogle Scholar
  11. 11.
    Hughes LB, et al. (2010) Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans. Arthritis Rheum. 62:3547–53.CrossRefGoogle Scholar
  12. 12.
    Elshazli R, Settin A. (2015) Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: a meta-analysis update. Immunobiology. 220:1012–24.CrossRefGoogle Scholar
  13. 13.
    Gregersen PK, Silver J, Winchester RJ. (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30:1205–13.CrossRefGoogle Scholar
  14. 14.
    Gorman JD, et al. (2004) Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients. Arthritis Rheum. 50:400–12.CrossRefGoogle Scholar
  15. 15.
    Viatte S, et al. (2015) Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA. 313:1645–56.CrossRefGoogle Scholar
  16. 16.
    Mattey DL, et al. (2007) Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study. Arthritis Rheum. 56:1408–16.CrossRefGoogle Scholar
  17. 17.
    Hughes LB, et al. (2008) The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum. 58:349–58.CrossRefGoogle Scholar
  18. 18.
    Reynolds RJ, et al. (2014) HLA-DRB1-Associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues. Arthritis Rheumatol. 66:3274–82.CrossRefGoogle Scholar
  19. 19.
    Lee HS, et al. (2004) Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901. Arthritis Rheum. 50:3468–75.CrossRefGoogle Scholar
  20. 20.
    Terao C, Raychaudhuri S, Gregersen PK. (2016) Recent advances in defining the Genetic basis of rheumatoid arthritis. Annu. Rev. Genomics Hum. Genet. 17:273–301.CrossRefGoogle Scholar
  21. 21.
    Weidinger S, Baurecht H, Naumann A, Novak N. (2010) Genome-wide association studies on IgE regulation: are genetics of IgE also genetics of atopic disease? Curr. Opin. Allergy Clin. Immunol. 10:408–17.CrossRefGoogle Scholar
  22. 22.
    Knevel R, et al. (2012) Genetic predisposition of the severity of joint destruction in rheumatoid arthritis: a population-based study. Ann. Rheum. Dis. 71:707–9.CrossRefGoogle Scholar
  23. 23.
    Maehlen MT, et al. (2011) FCRL3-169C/C genotype is associated with anti-citrullinated protein antibody-positive rheumatoid arthritis and with radiographic progression. J. Rheumatol. 38:2329–35.CrossRefGoogle Scholar
  24. 24.
    Marinou I, et al. (2007) Association of interleukin-6 and interleukin-10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody status. Arthritis Rheum. 56:2549–56.CrossRefGoogle Scholar
  25. 25.
    Cantagrel A, et al. (1999) Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis. Arthritis Rheum. 42:1093–100.CrossRefGoogle Scholar
  26. 26.
    Knevel R, et al. (2012) Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. Ann. Rheum. Dis. 71:1651–7.CrossRefGoogle Scholar
  27. 27.
    Teare MD, et al. (2013) Allele-dose association of the C5orf30 rs26232 variant with joint damage in rheumatoid arthritis. Arthritis Rheum. 65:2555–61.PubMedGoogle Scholar
  28. 28.
    Pawlik A, Wrzesniewska J, Florczak M, Gawronska-Szklarz B, Herczynska M. (2005) The -590 IL-4 promoter polymorphism in patients with rheumatoid arthritis. Rheumatol. Int. 26:48–51.CrossRefGoogle Scholar
  29. 29.
    Ceccarelli F, et al. (2011) Transforming growth factor beta 869C/T and interleukin 6–174G/C polymorphisms relate to the severity and progression of bone-erosive damage detected by ultrasound in rheumatoid arthritis. Arthritis Res. Ther. 13:R111.CrossRefGoogle Scholar
  30. 30.
    Song GG, Bae SC, Kim JH, Lee YH. (2014) Associations between TRAF1-C5 gene polymorphisms and rheumatoid arthritis: a meta-analysis. Immunol. Invest. 43:97–112.CrossRefGoogle Scholar
  31. 31.
    Ruyssen-Witrand A, et al. (2014) Association of IL-2RA and IL-2RB genes with erosive status in early rheumatoid arthritis patients (ESPOIR and RMP cohorts). Joint Bone Spine. 81:228–34.CrossRefGoogle Scholar
  32. 32.
    Mikuls TR, et al. (2006) Anti-cyclic citrullinated peptide antibody and rheumatoid factor isotypes in African Americans with early rheumatoid arthritis. Arthritis Rheum. 54:3057–9.CrossRefGoogle Scholar
  33. 33.
    Freedman BI, et al. (2014) End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 66:390–6.CrossRefGoogle Scholar
  34. 34.
    Bridges SL Jr, et al. (2010) Radiographic severity of rheumatoid arthritis in African Americans: results from a multicenter observational study. Arthritis Care Res. 62:624–31.CrossRefGoogle Scholar
  35. 35.
    Mikuls TR, et al. (2008) Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis. Ann. Rheum. Dis. 67:1529–34.CrossRefGoogle Scholar
  36. 36.
    Tang Q, et al. (2015) Expression of interferon-gamma receptor genes in peripheral blood mononuclear cells is associated with rheumatoid arthritis and its radiographic severity in African Americans. Arthritis Rheumatol. 67:1165–70.CrossRefGoogle Scholar
  37. 37.
    Pruim RJ, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 26:2336–7.CrossRefGoogle Scholar
  38. 38.
    Achim Zeileis CK, Jackman S. (2008) Regression models for count data in R. J. Stat. Softw. 27:1–25.Google Scholar
  39. 39.
    Kichaev G, et al. (2017) Improved methods for multi-trait fine mapping of pleiotropic risk loci. Bioinformatics. 33:248–55.CrossRefGoogle Scholar
  40. 40.
    Edwards W, Lindman H, Savage LJ. (1963) Bayesian statistical inference for psychological research. Psychol. Rev. 70:193–242.CrossRefGoogle Scholar
  41. 41.
    Gao X, Starmer J, Martin ER. (2008) A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet. Epidemiol. 32:361–9.CrossRefGoogle Scholar
  42. 42.
    Li MX, Yeung JM, Cherny SS, Sham PC. (2012) Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Hum. Genet. 131:747–56.CrossRefGoogle Scholar
  43. 43.
    Gao X, Becker LC, Becker DM, Starmer JD, Province MA. (2010) Avoiding the high Bonferroni penalty in genome-wide association studies. Genet. Epidemiol. 34:100–5.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Purcell S, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81:559–75.CrossRefGoogle Scholar
  45. 45.
    Trynka G, et al. (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nature Genet. 43:1193–201.CrossRefGoogle Scholar
  46. 46.
    Raychaudhuri S, et al. (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genet. 44:291–96.CrossRefGoogle Scholar
  47. 47.
    Barton A, et al. (2009) Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum. Mol. Gen. 18:2518–22.CrossRefGoogle Scholar
  48. 48.
    Stahl EA, et al. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genet. 42:508–14.CrossRefGoogle Scholar
  49. 49.
    Welter D, et al. (2014) The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42(Database issue):D1001–06.CrossRefGoogle Scholar
  50. 50.
    Ke X. (2012) Presence of multiple independent effects in risk loci of common complex human diseases. Am. J. Hum. Genet. 91:185–92.CrossRefGoogle Scholar
  51. 51.
    Knevel R, et al. (2013) Association of variants in IL2RA with progression of joint destruction in rheumatoid arthritis. Arthritis Rheum. 65:1684–93.CrossRefGoogle Scholar
  52. 52.
    Lowe CE, et al. (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genet. 39:1074–82.CrossRefGoogle Scholar
  53. 53.
    Yang W, et al. (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6:e1000841.CrossRefGoogle Scholar
  54. 54.
    Hiwatari M, et al. (2003) Fusion of an AF4-related gene, LAF4, to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23). Oncogene. 22:2851–5.CrossRefGoogle Scholar
  55. 55.
    Cen H, et al. (2012) Association of AFF1 rs340630 and AFF3 rs10865035 polymorphisms with systemic lupus erythematosus in a Chinese population. Immunogenetics. 64:935–8.CrossRefGoogle Scholar
  56. 56.
    Hinks A, et al. (2010) Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis. Genes Immun. 11:194–8.CrossRefGoogle Scholar
  57. 57.
    Jansen R, et al. (2017) Conditional eQTL analysis reveals allelic heterogeneity of gene expression. Hum. Mol. Genet. 26:1444–51.CrossRefGoogle Scholar
  58. 58.
    Lei C, et al. (2005) Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population. Eur. J. Hum. Genet. 13:823–8.CrossRefGoogle Scholar
  59. 59.
    Kormendy D, et al. (2013) Impact of the CTLA-4/CD28 axis on the processes of joint inflammation in rheumatoid arthritis. Arthritis Rheum. 65:81–7.CrossRefGoogle Scholar
  60. 60.
    Michel J, Langstein J, Hofstadter F, Schwarz H. (1998) A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur. J. Immunol. 28:290–5.CrossRefGoogle Scholar
  61. 61.
    Seo SK, et al. (2004) 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nature Med. 10:1088–94.CrossRefGoogle Scholar
  62. 62.
    van Steenbergen HW, et al. (2015) IL2RA is associated with persistence of rheumatoid arthritis. Arthritis Res. Ther. 17:244.CrossRefGoogle Scholar
  63. 63.
    Roifman CM. (2000) Human IL-2 receptor alpha chain deficiency. Pediatr. Res. 48:6–11.CrossRefGoogle Scholar
  64. 64.
    Dendrou CA, et al. (2009) Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet. 41:1011–15.CrossRefGoogle Scholar
  65. 65.
    Garrett-Sinha LA. (2013) Review of Ets1 structure, function, and roles in immunity. Cell. Mol. Life Sci. 70:3375–90.CrossRefGoogle Scholar
  66. 66.
    John SA, Clements JL, Russell LM, Garrett-Sinha LA. (2008) Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J. Biol. Chem. 283:951–62.CrossRefGoogle Scholar
  67. 67.
    Lu X, et al. (2015) Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression. Am. J. Hum. Genet. 96(5):731–9.CrossRefGoogle Scholar
  68. 68.
    Stranger BE, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 8:e1002639.CrossRefGoogle Scholar
  69. 69.
    Jiang L, et al. (2014) Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans. Arthritis Rheumatol. 66:1121–32.CrossRefGoogle Scholar

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Authors and Affiliations

  • Maria I. Danila
    • 1
    • 8
  • Vincent A. Laufer
    • 1
  • Richard J. Reynolds
    • 1
  • Qi Yan
    • 2
    • 3
  • Nianjun Liu
    • 4
  • Peter K. Gregersen
    • 5
  • Annette Lee
    • 5
  • Marlena Kern
    • 5
  • Carl D. Langefeld
    • 6
  • Donna K. Arnett
    • 7
  • S. Louis BridgesJr.
    • 1
  1. 1.Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Division of Pulmonary Medicine, Allergy and ImmunologyUniversity of PittsburghPittsburghUSA
  3. 3.Department of PediatricsUniversity of PittsburghPittsburghUSA
  4. 4.Department of Epidemiology and Biostatistics, School of Public HealthIndiana University BloomingtonBloomingtonUSA
  5. 5.Northwell HealthThe Feinstein Institute for Medical ResearchManhassetUSA
  6. 6.Wake Forest School of MedicineWake Forest UniversityWinston-SalemUSA
  7. 7.University of Kentucky College of Public HealthLexingtonUSA
  8. 8.Department of Medicine, Division of Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamUSA

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