Hum Hered 2005;60:109–118

Evidence for a Major Gene Influence on Tumor Necrosis Factor-α Expression in Tuberculosis: Path and Segregation Analysis

Stein C.M.a-c · Nshuti L.b, d · Chiunda A.B.a, b · Boom W.H.b · Elston R.C.a · Mugerwa R.D.b, d · Iyengar S.K.a · Whalen C.C.a-c
aDepartment of Epidemiology and Biostatistics, bTuberculosis Research Unit, and cCenter for Modern Epidemiology of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA; dClinical Epidemiology Unit, Makerere University School of Medicine, Kampala, Uganda
email Corresponding Author

 goto top of outline Key Words

  • Shared environment
  • Infectious disease
  • Heritability
  • Cytokine
  • Phenotype modeling
  • Immunogenetics

 goto top of outline Abstract

Objective: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. Methods: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-α (TNFα) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. Results: Path analysis, conducted to assess the effect of shared environment, suggested that TNFα is heritable (narrow sense heritability = 34–66%); the effect of shared environment is minimal (1–14%), but gene-environment interaction may be involved. Segregation analysis of TNFα suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Conclusion: Our data further support TNFα as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.

Copyright © 2005 S. Karger AG, Basel

 goto top of outline References
  1. Raviglione MC, Snider DE, Kochi A: Global epidemiology of tuberculosis: Morbidity and mortality of a worldwide epidemic. JAMA 1995;273:220–226.
  2. Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, Schreiber R, Mak TW, Bloom BR: Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2:561–572.
  3. Kramnik I, Dietrick WF, Demant P, Bloom BR: Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci 2000;97:8560–8565.
  4. Skamene E, Schurr E, Gros P: Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections. Annu Rev Med 1998;49:275–287.
  5. Comstock GW: Tuberculosis in twins: a re-analysis of the Prophit Study. Am Rev Resp Dis 1978;117:621–624.
  6. Kallmann FJ, Reisner D: Twin studies on the significance of genetic factors in tuberculosis. Am Rev Tuberculosis 1943;47:549–574.
  7. Shaw MA, Collins A, Peacock CS: Miller EN, Black GF, Sibthorpe D, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM: Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tuberc Lung Dis 1997;78:35–45.
  8. Bellamy R: Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun 2003;4:4–11.
  9. Bellamy R, Beyers N, McAdam KPWJ, Ruwende C, Gie R, Samaai P, Bester D, Meyer M, Corrah T, Collin M, Camidge DR, Wilkinson D, Hoal-van Helden E, Whittle HC, Amos W, van Helden PD, Hill AVS: Genetic susceptibility to tuberculosis in Africans: A genome-wide scan. Proc Natl Acad Sci 2000;97:8005–8009.
  10. Cervino ACL, Lakiss S, Sow O, Bellamy R, Beyers N, Hoal-van Helden E, van Helden PD, McAdam KPWJ, Hill AVS: Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families. Hum Mol Genet 2002;11:1599–1603.
  11. Greenwood CMT, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier E, Fanning EA, Schurr E, Morgan K: Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 2000;67:405–416.
  12. Jamieson SE, Miller EN, Black GF, Peacock CS, Cordell HJ, Howson JMM, Shaw MA, Burgner D, Xu W, Lins-Lainson Z, Ramos F, Silveira F, Blackwell JM: Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 2004;5:46–57.
  13. Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, Cordell HJ, Shaw MA, Lins-Lainson Z, Ramos F, Silveira F, Blackwell JM: Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 2004;5:63–67.
  14. Comstock GW: Epidemiology of tuberculosis. Am Rev Resp Dis 1982;125:8–15.
  15. Stein CM, Guwattude D, Nakakeeto M, Peters P, Elston RC, Tiwari HK, Whalen CC: Heritability Analysis of Cytokines as Intermediate Phenotypes of Tuberculosis. J Infect Dis 2003;187:1679–1685.
  16. Barnes PF, Fong SJ, Brennan PJ, Twomey PE, Mazumder A, Modlin RL: Local production of tumor necrosis factor and IFN-gamma in tuberculosis pleuritis. J Immunol 1990;145:149–154.
  17. Roach DR, Bean AGD, Demangel C, France MP, Briscoe H, Britton WJ: TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620–4627.
  18. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kaszinca J, Schwietermann WD, Siegel JN, Braun MM: Tuberculosis associated with inflixamab, a tumor necrosis factor a-neutralizing agent. N Engl J Med 2001;345:1098–1104.
  19. Rice JP, Saccone NL, Rasmussen E: Definition of the phenotype. Adv Genet 2001;42:69–76.
  20. Schork NJ: Genetics of complex disease: Approaches, problems, and solutions. Am J Respir Crit Care Med 1997;156:S103–S109.
  21. Duggirala R, Williams JT, Williams-Blangero S, Blangero J: A variance components approach to dichotomous trait linkage using a threshold model. Genet Epidemiol 1997;14:987–992.
  22. Cloninger CR, Rao DC, Rice J, Reich T, Morton NE: A defense of path analysis in genetic epidemiology. Am J Hum Genet 1983;35:733–756.
  23. Rao DC, Rice T: Path analysis in genetics; in Armitage P, Colton T (eds): Encyclopedia of Biostatistics. Chichester, John Wiley & Sons, 1999.
  24. McGue M, Gottesman II, Rao DC: Resolving genetic models for the transmission of schizophrenia. Genet Epidemiol 1985;2:99–110.
  25. Rao DC, Morton NE, Gottesman II, Lew R: Path analysis of qualitative data on pairs of relatives: Application to schizophrenia. Hum Hered 1981;31:325–333.
  26. Rice T, Vogler GP, Laskarzewski PM, Perry TS, Rao DC: Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Stanford Lipid Research Clinics Family Study. Am J Med Genet 1991;39:270–277.
  27. Guwattude D, Nakakeeto M, Jones-Lopez EC, Maganda A, Chiunda A, Mugerwa RD, Ellner JJ, Bukenya G, Whalen CC: Tuberculosis in household contacts of infectious cases in Kampala, Uganda. Am J Epidemiol 2003;158:887–898.

    External Resources

  28. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O’Brien RJ, Reves RR, Reichman LB, Simone RM, Starke JR, Vernon AA: American Thoracic Society / Centers for Disease Control and Prevention / Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662.
  29. Rao DC, Morton NE, Cloninger CR: Path analysis under generalized assortative mating. I. Theory. Genet Res Comb 1979;33:175–188.
  30. Rao DC, Morton NE, Yee S: Resolution of cultural and biological inheritance by path analysis. Am J Hum Genet 1976;28:228–242.
  31. Rao DC, Wette R: Environmental index in genetic epidemiology: An investigation of its role, adequacy, and limitations. Am J Hum Genet 1990;46:168–178.
  32. Carey G: A general multivariate approach to linear modeling in human genetics. Am J Hum Genet 1986;39:775–786.
  33. Hatcher L: A step-by-step approach to using SAS for factor analysis and structural equation modeling. Cary, NC: SAS Publishing, 1994.
  34. SAS/STAT. Cary, NC, 2001.
  35. Akaike H: Information theory and an extension of the maximum likelihood principle; in Petrov BN, Csaki F (eds): Proceedings of the Second International Symposium on Information Theory. Budapest, Akademiai Kiado, 1973, pp 267–281.
  36. Kwon JM, Boehnke M, Burns TL, Moll PP: Commingling and segregation analyses: comparison of results from a simulation study of a quantitative trait. Genet Epidemiol 1990;7:57–68.
  37. Bonney GE: On the statistical determination of major gene mechanisms in continuous human traits: Regressive models. Am J Med Genet 1984;18:731–749.
  38. Li Z, Bonney GE, Rao DC: Genetic analysis combining path analysis with regressive models: The BETA path model of polygenic and familial environment transmission. Genet Epidemiol 1994;11:431–442.
  39. Fernando RL, Stricker C, Elston RC: The finite polygenic mixed model: An alternative formulation for the mixed model of inheritance. Theor Appl Genet 1994;88:573–580.
  40. Stein CM: Genetic and environmental influences on tuberculosis susceptibility. Doctoral dissertation, Case Western Reserve University, 2004.
  41. Chapman JS, Dyerly MD: Social and other factors in intrafamilial transmission of tuberculosis. Am Rev Respir Dis 1964;90:48–60.
  42. Riley RL, Mills CC, Nyka W, Weinstock N, Storey PB, Sultan LU, Riley MC, Wells WF: Aerial dissemination of pulmonary tuberculosis: A two-year study of contagion in a tuberculosis ward. Am J Hyg 1959;70:185–196.
  43. Lienhardt C, Fielding K, Sillah J, Tunkara A, Donkor S, Manneh K, Warndorff D, McAdam KPWJ, Bennett S: Risk factors for tuberculosis infection in sub-Saharan Africa: A contact study in The Gambia. Am J Respir Crit Care Med 2003;168:448–455.
  44. Marks SM, Taylor Z, Qualls NL, Shrestha-Kuwahara RJ, Wilce MA, Nguyen CH: Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 2000;162:2033–2038.
  45. Ma X, Wright JA, Reich RA, Teeter LD, El Sahly HM, Awe RJ, Musser JM, Graviss EA: 5′ dinucleotide repeat polymorphism of NRAMP1 and susceptibility to tuberculosis among Caucasian patients in Houston, Texas. Int J Tuberc Lung Dis 2002;6:818–823.
  46. Fitness J, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Fine PEM, Hill AVS: Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of Northern Malawi. Am J Trop Med Hyg 2004;71:341–349.
  47. Bornman L, Campbell SJ, Fielding K, Bah B, Sillah J, Gustafson P, Manneh K, Lisse I, Allen A, Sirugo G, Sylla A, Aaby P, McAdam KPWJ, Bah-Sow O, Bennett S, Lienhardt C, Hill AVS: Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: A case-control study. J Infect Dis 2004;190:1631–1641.
  48. Stead WW: Variation in vulnerability to tuberculosis in America today: random, or legacies of different ancestral epidemics? Int J Tuberc Lung Dis 2001;5:807–814.
  49. Louie LG, Hartogensis WE, Jackman RP, Schultz KA, Zijenah LS, Yiu C H-Y, Nguyen VD, Sohsman MY, Katzenstein DK, Mason PR: Mycobacterium tuberculosis/HIV-1 coinfection and disease: Role of human leukocyte antigen variation. J Infect Dis 2004;189:1084–1090.
  50. Fan J, Wu Y, Fossella JA, Posner MI: Assessing the heritability of attentional networks. BMC Neurosci 2001;2:14.
  51. Janský L, Reymanová P, Kopecký J: Dynamics of cytokine production in human peripheral blood mononuclear cells stimulated by LPS or infected by Borrelia. Physiol Res 2003;52:593–598.

 goto top of outline Author Contacts

Christopher C. Whalen, MD, MS
Department of Epidemiology and Biostatistics
Case Western Reserve University
10900 Euclid Avenue, Cleveland, OH 44106 (USA)
Tel. +1 216 368 4192, Fax +1 216 368 0883, E-Mail

 goto top of outline Article Information

CCW and SKI contributed equally as senior authors of this work.

Received: June 21, 2005
Accepted: August 18, 2005
Published online: October 13, 2005
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 6, Number of References : 51

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 2, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information:

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.