- Catherine M. Stein1,3,4,
- Sarah Zalwango3,5,
- Allan B. Chiunda1,3,
- Christopher Millard1,
- Dmitry V. Leontiev1,
- Amanda L. Horvath1,
- Kevin C. Cartier1,
- Keith Chervenak3,
- W. Henry Boom3,
- Robert C. Elston1,
- Roy D. Mugerwa3,5,
- Christopher C. Whalen2,3,4 &
- …
- Sudha K. Iyengar1
570Accesses
Abstract
Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-α (TNFα) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFα regulation and found that interleukin(IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFα receptor 1 (TNFR1) genes were linked and associated to both TB and TNFα. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB andTNFR1 in a human population and our findings forIL-10 andIFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits.
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References
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P (2005) A haplotype map of the human genome. Nature 437:1299–1320
Awomoyi A, Marchant A, Howson J, McAdam K, Blackwell J, Newport M (2002) Interleukin-10, Polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis. J Infect Dis 186:1808–1814
Awomoyi AA, Nejentsev S, Richardson A, Hull J, Koch O, Podinovskaia M, Todd JA, McAdam KPWJ, Blackwell JM, Kwiatkowski D, Newport MJ (2004) No association between interferon-γ receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample. Thorax 59:291–294
Balcewicz-Sablinska M, Gan H, Remold H (1999) Interleukin 10 produced by macrophages inoculated withMycobacterium avium attenuates mycobacteria-induced apoptosis by reduction of TNF-α activity. J Infect Dis 180:1230–1237
Barnes P, Fong S, Brennan P, Twomey P, Mazumder A, Modlin R (1990) Local production of tumor necrosis factor and IFN-gamma in tuberculosis pleuritis. J Immunol 145:149–154
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Bekker LG, Haslett P, Maartens G, Steyn L, Kaplan G (2000) Thalidomide-induced antigen-specific immune stimulation in patients with human immunodeficiency virus type 1 and tuberculosis. J Infect Dis 181:954–965
Bellamy R (2003) Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun 4:4–11
Bellamy R, Ruwende C, Corrah T, McAdam K, Whittle H, Hill A (1998) Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis. Tuberc Lung Dis 79:83–89
Blackwell J, Barton C, White J, Searle S, Baker A, Williams H, Shaw M (2004) Genomic organizaton and sequence of the human NRAMP gene: identification and mapping of a promotor region polymorphism. Mol Med 1:194–205
Blumberg H, Burman W, Chaisson R, Daley C, Etkind S, Friedman L, Fujiwara P, Grzemska M, Hopewell P, Iseman M, Jasmer R, Koppaka V, Menzies R, O’Brien R, Reves R, Reichman L, Simone R, Starke J, Vernon A, American Thoracic Society, Centers for Disease Control, Prevention, Infectious Diseases Society (2003) American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 167:603–662
Bochud P-Y, Hawn T, Aderem A (2003) Cutting edge: a toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol 170:3451–3454
Centers for Disease Control and Prevention (2003) Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Soceity of America. MMWR 52:1–77
Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G, Bennett S, McAdam KP, Sow O, Lienhardt C, Hill AV (2006) Polymorphism within the interferon gamma/receptor complex is associated with pulmonary tuberculosis. Am J Respir Crit Care Med 174:339–343
Delgado J, Baena A, Thim S, Goldfeld A (2002) Ethnic-specific genetic associations with pulmonary tuberculosis. J Infect Dis 186:1463–1468
Drennan M, Nicolle D, Quesniaux V, Jacobs M, Allie N, Mpagi J, Frémond C, Wagner H, Kirschning C, Ryffel B (2004) Toll-like receptor 2-deficient mice succumb toMycobacterium tuberculosis infection. Am J Pathol 164:49–57
Duggirala R, Williams J, Williams-Blangero S, Blangero J (1997) A variance components approach to dichotomous trait linkage using a threshold model. Genet Epidemiol 14:987–992
Elston RC, George VT, Severtson F (1992) The Elston–Stewart algorithm for continuous genotypes and environmental factors. Hum Hered 42:16–27
Epstein M, Duren W, Boehnke M (2000) Improved inference of relationship for pairs of individuals. Am J Hum Genet 67:1219–1231
Fitness J, Floyd S, Warndorff D, Sichali L, Malema S, Crampin A, Fine P, Hill A (2004) Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of Nothern Malawi. Am J Trop Med Hyg 71:341–349
Flores-Villanueva PO, Ruiz-Morales JA, Song CH, Flores LM, Jo EK, Montano M, Barnes PF, Selman M, Granados J (2005) A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis. J Exp Med 202:1649–1658
Flynn J, Goldstein M, Chan J, Triebold K, Pfeffer K, Lowenstein C, Schreiber R, Mak T, Bloom B (1995) Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561–572
Formica S, Roach T, Blackwell J (1994) Interaction with extracellular matrix proteins influences Lsh/Ity/Bcg (candidate Nramp) gene regulation of macrophage priming/activation for tumor necrosis factor-α and nitrite release. Immunology 82:42–50
Fraser D, Bulat-Kardum L, Knezevic J, Babarovic P, Matakovic-Mileunic N, Dellacasagrande J, Matanic D, Pavelic J, Beg-Zec Z, Dembic Z (2003) Interferon-γ receptor-1 gene polymorphism in tuberculosis patients from Croatia. Scand J Immunol 57:480–484
George V, Elston RC (1987) Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet Epidemiol 4:193–202
Goddard K, Witte J, Suarez B, Catalona W, Olson J (2001) Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 68:1197–1206
Goldman M, Marchant A, Schandené L (1996) Endogenous interleukin-10 in inflammatory disorders: Regulatory roles and pharmacological modulation. Ann NY Acad Sci 796:282–293
Gray-McGuire C (2004) Assessment of a variance component method for binary phenotype data: model misspecification and effects of ascertainment. PhD Dissertation, Case Western Reserve University
Guwattude D, Nakakeeto M, Jones-Lopez E, Maganda A, Chiunda A, Mugerwa R, Ellner J, Bukenya G, Whalen C (2003) Tuberculosis in household contacts of infectious cases in Kampala, Uganda. Am J Epidemiol 158:887–898
Haseman J, Elston R (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2:3–19
Janeway C, Travers P, Walport M, Shlomchik M (2001) Immunobiology, 5th edn. Garland Publishing, New York
Keane J, Gershon S, Wise R, Mirabile-Levens E, Kaszinca J, Schwietermann W, Siegel J, Braun M (2001) Tuberculosis associated with inflixamab, a tumor necrosis factor α-neutralizing agent. N Engl J Med 345:1098–1104
Knight J, Kwiatkowski D (1999) Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proc Assoc Am Phys 111:290–298
Kong X, Murphy K, Raj T, He C, White P, Matise T (2004) A combined linkage-physical map of the human genome. Am J Hum Genet 75:1143–1148
Kurreeman FA, Schonkeren JJ, Heijmans BT, Toes RE, Huizinga TW (2004) Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level. Hum Mol Genet 13:1755–1762
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247
Li HT, Zhang TT, Zhou YQ, Huang QH, Huang J (2006) SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int J Tuberc Lung Dis 10:3–12
López-Maderuelo D, Arnalich F, Serantes R, González A, Codeoceo R, Madero R, Vazquez J, Montiel C (2003) Interferon-γ and interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med 167:970–975
Means T, Wang S, Lien E, Yoshimura A, Golenbock D, Fenton M (1999) Human Toll-like receptors mediate ceulluar activation byMycobacterium tuberculosis. J Immunol 163:3920–3927
Means T, Jones B, Schromm A, Shurtleff B, Smith J, Keane J, Golenbock D, Vogel S, Fenton M (2001) Differential effects of a toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. J Immunol 166:4074–4082
Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M (1996) A mutation in the interferon-γ-receptor gene and susceptbility to mycobacterial infection. New Engl J Med 335:1941–1949
Olson J (1999) A general conditional-logistic model for affected-relative-pair linkage studies. Am J Hum Genet 65:1760–1769
Peschon JJ, Torrance DS, Stocking KL, Glaccum MB, Otten C, Willis CR, Charrier K, Morrissey PJ, Ware CB, Mohler KM (1998) TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J Immunol 160:943–952
Piguet PF, Da Kan C, Vesin C (2002) Rolle of tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice. Lab Invest 82:1155–1166
Pociot F, Briant L, Jongeneel CV, Mölvig J, Worsaae H, Abbal M, Thomsen M, Nerup J, Cambon-Thomsen A (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-α and TNF-β by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23:224–231
Raviglione M, Snider D, Kochi A (1995) Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 273:220–226
Ribeiro-Rodrigues R, Resende CT, Johnson JL, Ribeiro F, Palaci M, Sa RT, Maciel EL, Pereira Lima FE, Dettoni V, Toossi Z, Boom WH, Dietze R, Ellner JJ, Hirsch CS (2002) Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance. Clin Diagn Lab Immunol 9:818–823
Rice JP, Saccone NL, Rasmussen E (2001) Definition of the phenotype. Adv Genet 42:69–76
Risch N (2000) Searching for genetic determinants in the new millenium. Nature 405:847–856
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517
Roach DR, Bean AGD, Demangel C, France MP, Briscoe H, Britton WJ (2002) TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 168:4620–4627
S.A.G.E. (2006) Statistical analysis for genetic epidemiology. Case Western Reserve University, Cleveland, OH
Scola L, Crivello A, Marino V, Gioia V, Serauto A, Candore G, Colonna-Romano G, Caruso C, Lio D (2003) IL-10 and TNF-alpha polymorphisms in a sample of Sicilian patients affected by tuberculosis: implication for ageing and life span expectancy. Mech Ageing Dev 124:569–572
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
Shin HD, Park BL, Kim YH, Cheong HS, Lee IH, Park SK (2005) Common interleukin 10 polymorphism associated with decreased risk of tuberculosis. Exp Mol Med 37:128–132
Skamene E, Schurr E, Gros P (1998) Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections. Annu Rev Med 49:275–287
Stein CM, Guwattude D, Nakakeeto M, Peters P, Elston RC, Tiwari HK, Whalen CC (2003) Heritability analysis of cytokines as intermediate phenotypes of tuberculosis. J Infect Dis 187:1679–1685
Stein CM, Nshuti L, Chiunda AB, Boom WH, Elston RC, Mugerwa RD, Iyengar SK, Whalen CC (2005) Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis. Hum Hered 60:109–118
Tso H, Ip W, Chong W, Tam C, Chiang A, Lau Y (2005) Association of interferon gamma and interleukin 10 genes with tuberculosis in Hong Kong Chinese. Genes Immun 6:358–363
Underhill DM, Ozinsky A, Smith KD, Aderem A (1999) Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc Natl Acad Sci 96:14459–14463
van Crevel R, Ottenhoff THM, van der Meek JWM (2002) Innate immunity to mycobacterium tuberculosis. Clin Microbiol Rev 15:294–309
Wigginton JE, Abecasis GR (2005) PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21:3445–3447
Wilson AG, Symons JA, McDowel TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor α promotor on transcriptional activation. Proc Natl Acad Sci 94:3195–3199
Witte JS, Elston RC, Schork NJ (1996) Genetic dissection of complex traits. Nat Genet 12:355–356
Acknowledgments
This study would not be possible without the support of the Ugandan National Tuberculosis and Leprosy Control Programme, the generous participation of the Ugandan patients and families, and the medical officers, project coordinators, laboratory personnel and home health visitors who helped collect the epidemiological data. This work is supported in part by the National Institutes of Health, National Center for Research Resources (NCRR) Multidisciplinary Clinical Research Career Development Programs Grant (8K12RR023264), Tuberculosis Research Unit (grant N01-AI95383 from the NIAID), National Institute of General Medical Sciences (GM-28356), a developmental grant from the STERIS Corporation, and the Gene Expression and Genotyping Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland (P30 CA43703). Some of the results of this paper were obtained by using the program package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the NCRR.
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Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building Room 1303, 2103 Cornell Rd, Cleveland, OH, 44106, USA
Catherine M. Stein, Allan B. Chiunda, Christopher Millard, Dmitry V. Leontiev, Amanda L. Horvath, Kevin C. Cartier, Robert C. Elston & Sudha K. Iyengar
Department of Epidemiology and Biostatistics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA
Christopher C. Whalen
Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH, USA
Catherine M. Stein, Sarah Zalwango, Allan B. Chiunda, Keith Chervenak, W. Henry Boom, Roy D. Mugerwa & Christopher C. Whalen
Center for Modern Epidemiology of Infectious Diseases, Case Western Reserve University, Cleveland, OH, USA
Catherine M. Stein & Christopher C. Whalen
Clinical Epidemiology Unit, Makerere University School of Medicine, Kampala, Uganda
Sarah Zalwango & Roy D. Mugerwa
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C. C. Whalen and S. K. Iyengar contributed equally as senior authors of this work.
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Stein, C.M., Zalwango, S., Chiunda, A.B.et al. Linkage and association analysis of candidate genes for TB and TNFα cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes.Hum Genet121, 663–673 (2007). https://doi.org/10.1007/s00439-007-0357-8
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