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Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

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Abstract

Sarcoidosis, a systemic granulomatous disease, likely results from both environmental agents and genetic susceptibility. Sarcoidosis is more prevalent in women and, in the United States, African Americans are both more commonly and more severely affected than Caucasians. We report a follow up of the first genome scan for sarcoidosis susceptibility genes in African Americans. Both the genome scan and the present study comprise 229 African American nuclear families ascertained through two or more sibs with sarcoidosis. Regions studied included those which reached a significance in the genome scan of 0.01 (2p25, 5q11, 5q35, 9q34, 11p15 and 20q13), 0.05 (3p25 and 5p15–13) or which replicated previous findings (3p14–11). We performed genotyping with additional markers in the same families used in the genome scan. We examined multi-locus models for epistasis and performed model-based linkage analysis on subsets of the most linked families to characterize the underlying genetic model. The strongest signal was at marker D5S407 (P=0.005) on 5q11.2, using both full and half sibling pairs. Our results support, in an African American population, a sarcoidosis susceptibility gene on chromosome 5q11.2, and a gene protective for sarcoidosis on 5p15.2. These fine mapping results further prioritize the importance of candidate regions on chromosomes 2p25, 3p25, 5q35, 9q34, 11p15 and 20q13 for African Americans. Additionally, our results suggest joint action of the effects of putative genes on chromosome 3p14–11 and 5p15.2. We conclude that multiple susceptibility loci for sarcoidosis exist in African Americans and that some may have interdependent effects on disease pathogenesis.

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References

  • Bade B, Lohrmann J, Ten Brinke A et al (2005) Detection of soluable human granzyme K in vitro and in vivo. Eur J Immunol 35:2940–2948

    Article  PubMed  CAS  Google Scholar 

  • Dillon SR, Sprecher C, Hammond A et al (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5:752–760

    Article  PubMed  CAS  Google Scholar 

  • Dourado M, Bento J, Mesquita L et al (2005) [Granzymes A and B in pulmonary sarcoidosis (experimental study)]. Rev Port Pneumol 11:111–133

    PubMed  Google Scholar 

  • Dunner E, Williams JH Jr (1961) Epidemiology of sarcoidosis in the United States. Am Rev Respir Dis 84(5)2:163–168

    Google Scholar 

  • Elston RC, Stewart J (1971) A general model for the genetic analysis of pedigree data. Hum Hered 21:523–542

    Article  PubMed  CAS  Google Scholar 

  • Elston RC, Song D, Iyengar S (2005) Mathematical assumptions versus biological reality: Myths in affected sib pair linkage analysis. Am J Hum Genet 76:152–156

    Article  PubMed  CAS  Google Scholar 

  • Grutters JC (2003) Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 20:20–27

    PubMed  Google Scholar 

  • Haseman JK, Elston RC (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2:24–31

    Article  Google Scholar 

  • Iannuzzi MC, Iyengar SK, Gray-McGuire C et al (2005) Genome-wide search for sarcoidosis susceptibility genes in African Americans. Genes Immun 6:509–518

    Article  PubMed  CAS  Google Scholar 

  • Ito H, Takazoe M, Fukuda Y, et al (2004) A pilot randomized trial of a human anti-interleukin-6 receptor nmonoclonal antibody in active Crochn’s disease. Gastroenterology 126:989–996 discussion 947

    Google Scholar 

  • Jones SA, Richards PJ, Scheller J, Rose-John S (2005) IL-6 transsignaling: the in vivo consequences. J Interferon Cytokine Res 25:241–253

    Article  PubMed  CAS  Google Scholar 

  • Liou ML, Liou HC (1999) The ubiquitin-homology protein, DAP-1, associates with tumor necrosis factor receptor (p60) death domain and induces apoptosis. J Biol Chem 274:10145–10153

    Article  PubMed  CAS  Google Scholar 

  • Mermigkis C, Polychronopoulos V, Mermigkis D et al (2005) Overexpression of Bcl-2 protein in bronchoalveolar lavage lymphocytes and macrophages in sarcoidosis. Respiration

  • Mihara M, Takagi N, Takeda Y, Ohsugi Y (1998) IL-6 receptor blockage inhibits the onset of autoimmunune kidney disease in NZB/W F1 mice. Clin Exp Immunol 112:397–402

    Article  PubMed  CAS  Google Scholar 

  • Mihara M, Kotoh M, Nishimoto N et al (2001) Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys. Clin Immunol 98:319–326

    Article  PubMed  CAS  Google Scholar 

  • Moller DR, Forman JD, Liu MC et al (1996) Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 156:4952–4960

    PubMed  CAS  Google Scholar 

  • Newman LS, Rose CS, Bresnitz EA et al (2004) A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 170:1268–1269

    Article  Google Scholar 

  • Raveh T, Berissi, H Eisenstein M, Spivak T, Kimchi A (2000) A functional genetic screen identifies regions at the C-terminal tail and death domain of death-associated protein kinase that are critical for its proapoptotic activity. Proc Natl Acad Sci USA 97:1572–1577

    Article  PubMed  CAS  Google Scholar 

  • Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Ianuzzi MC (1997) Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Eidemiol 145:234–241

    CAS  Google Scholar 

  • Rybicki BA, Iannuzzi MC, Frederick MM et al (2001a) Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 164:2085–2091

    CAS  Google Scholar 

  • Rybicki BA, Kirkey KL, Major M et al (2001b) Familial risk ratio of sarcoidosis in African–American sibs and parents. Am J Epidemiol 153:188–193

    Article  CAS  Google Scholar 

  • Rybicki BA, Hirst K, Iyengar SK, Barnard JG, Judson MA, Rose CS, Donohue JF, Kavuru MS, Rabin DL, Rossman MD, Baughman RP, Elston RC, Maliarik MJ, Moller DR, Newman LS, Teirstein AS, Iannuzzi MC (2005) A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study. Sarcoidosis Vasc Diffuse Lung Dis 22:115–122

    PubMed  Google Scholar 

  • Schaid DJ, Elston RC, Tran L, Wilson AF (2000) Model-free sib-pair linkage analysis: combining full-sib and half-sib pairs. Genet Epi 19:30–51

    Article  CAS  Google Scholar 

  • Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, Muller-Quernheim J, Schwinger E (2001) Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med 164:840–846

    PubMed  CAS  Google Scholar 

  • Shete S, Jacobs KB, Elston RC (2003) Adding further power to the Haseman and Elston method for detecting linkage in larger sibships: weighting sums and differences. Hum Hered 55:79–85

    Article  PubMed  Google Scholar 

  • S A G E (2004) Statistical Analysis for Genetic Epidemiology, Release 5.0

  • Stridh H, Plank A, Gigliotti D, Eklund A, Grunewald J (2002) Apoptosis resistance bronchoalveolar lavage (BAL) fluid lymphocytes in sarcoidosis. Thorax 57:897–901

    Article  PubMed  CAS  Google Scholar 

  • Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819

    Article  PubMed  CAS  Google Scholar 

  • Takagi N, Mihara M, Moriya Y et al (1998) Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 41:2117–2121

    Article  PubMed  CAS  Google Scholar 

  • Terris M, Chaves AD (1966) An epidemiologic study of sarcoidosis. Am Rev Respir Dis 94:50–55

    PubMed  CAS  Google Scholar 

  • Wang T, Elston RC (2004) A modified revisted Haseman–Elston method to further improve power. Hum Hered 57:109–116

    Article  PubMed  Google Scholar 

  • Wendling D, Racadot E, Wijdenes J (1993) Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol 20:259–262

    PubMed  CAS  Google Scholar 

  • Wiltshire S, Morris AP, McCarthy MI, Cardon LR (2005) How useful is the fine-scale mapping of complex trait linkage peaks? Evaluating the impact of additional microsatellite genotyping on the posterior probability of linkage. Genet Epidemiol 28:1–10

    Article  PubMed  Google Scholar 

  • Xaus J, Besalduch N, Comalada M et al (2003) High expression of p21 Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation. J Leukoc Biol 74:295–301

    Article  PubMed  CAS  Google Scholar 

  • Xing C, Elston RC (2006) Distribution and magnitude of type I error of model-based multipoint lod scores: implications for multipoint mod scores. Genet Epidemiol (in press)

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Acknowledgments

We thank all of the family members who participated in our study. This work was supported by the National Institutes of Health Grants UO1 HL060263, RO1 GM28356 and P41 RR003655.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

    Courtney Gray-McGuire, Ritwik Sinha, Sudha Iyengar, Christopher Millard & Robert C. Elston

  2. Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI, USA

    Benjamin A. Rybicki

  3. Division of Pulmonary, Critical Care, and Sleep Medicine, Mt. Sinai School of Medicine, 1 Gustave Levy Place, Box 1232, New York, NY, 10029, USA

    Michael C. Iannuzzi

Authors
  1. Courtney Gray-McGuire
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  2. Ritwik Sinha
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  3. Sudha Iyengar
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  4. Christopher Millard
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  5. Benjamin A. Rybicki
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  6. Robert C. Elston
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  7. Michael C. Iannuzzi
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Consortia

SAGA Study Consortium

Corresponding author

Correspondence to Michael C. Iannuzzi.

Appendix: The Sarcoidosis Genetic Analysis (SAGA) Study Consortium

Appendix: The Sarcoidosis Genetic Analysis (SAGA) Study Consortium

Clinical Centers Core

Cleveland Clinic: Mani S. Kavuru, M.D.; Chenett Johnson.; Nancy Ivansek

Emory University: Samuel M. Aguayo, M.D.; Gloria Westney, M.D.; Kathleen A.S. Cannella, R.N., Ph.D.; Francesca Cordi.

Georgetown University Medical Center: David L. Rabin, M.D.; Henry Yeager, Jr., M.D.; Lisa Stewart; Kemi Odegbile; Tameka Weerasingna.

Henry Ford Health System: Michael C. Iannuzzi, M.D.; Benjamin A. Rybicki, Ph.D.; Wanda Bibbs, R.N.; Marcie Major, R.N.

Johns Hopkins University School of Medicine: David R. Moller, M.D.; Rebecca Robinson

Medical University of South Carolina: Marc A. Judson, M.D.; Angela Anderson, R.N.

Mount Sinai Medical Center: Alvin S. Teirstein, M.D.; Louis DePalo, M.D.; Romena Rouf.

National Jewish Medical and Research Center: Lee S. Newman, M.D., M.A.; Cecile Rose, M.D., M.P.H.; Juliana Barnard, M.A.; Lori Silveira, M.S.; Rosalind Dudden, MLS, DM/AHIP; Ben Lee, Lynn Morehead.

University of Cincinnati Medical Center: Robert P. Baughman, M.D.; Donna B. Winget.

University of North Carolina: James F. Donohue, M.D.; Julie Montenegro, R.N.; Jeanie Mascarella, RN, MSN.

University of Pennsylvania and Medical College of Pennsylvania - Hahnemann University Medical Centers: Milton D. Rossman, M.D.; Jackie Regovich, M.P.H.

Data Coordinating Center

George Washington University: Kathryn Hirst, Ph.D., Sarah Fowler, Ph.D., Robin Laney, Laure Blghormli, M.S.

Genetics Core

Henry Ford Health System (DNA Core Laboratory): Mary Maliarik, Ph.D.

Case Western Reserve University (Genotyping Laboratory and Genetic Analysis): Robert C. Elston, Ph.D.; Sudha Iyengar, Ph.D.; Courtney Gray-McGuire, Ph.D., Trent Harris.

National Heart, Lung, And Blood Institute

National Heart, Lung, and Blood Institute: Sandra Hatch, Ph.D.

Data Safety and Monitoring Board

David Center, M.D. (Chair)

Rodney Go, Ph.D.

Christine Grady, R.N., Ph.D.

Talmadge King, Jr., M.D.

William Nichols, Ph.D.

Study Chairman

Michael C. Iannuzzi, M.D.

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Gray-McGuire, C., Sinha, R., Iyengar, S. et al. Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5. Hum Genet 120, 420–430 (2006). https://doi.org/10.1007/s00439-006-0201-6

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  • DOI: https://doi.org/10.1007/s00439-006-0201-6

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