Heritability analysis of cytokines as intermediate phenotypes of tuberculosis

J Infect Dis. 2003 Jun 1;187(11):1679-85. doi: 10.1086/375249. Epub 2003 May 9.


Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-alpha, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-gamma, TNF-alpha, and TGF-beta reflected the immunologic model of TB. In this analysis, the first component explained >38% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Cytokines / blood*
  • Cytokines / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Interferon-gamma / blood
  • Interferon-gamma / genetics
  • Linear Models
  • Male
  • Mycobacterium tuberculosis
  • Pedigree
  • Phenotype
  • Quantitative Trait, Heritable*
  • Transforming Growth Factors / blood
  • Transforming Growth Factors / genetics
  • Tuberculosis / blood
  • Tuberculosis / genetics*
  • Tuberculosis / immunology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / genetics
  • Uganda


  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Transforming Growth Factors
  • Interferon-gamma