Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis

Clin Infect Dis. 2013 Oct;57(7):963-70. doi: 10.1093/cid/cit438. Epub 2013 Jun 25.


Background: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy.

Methods: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis.

Results: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ.

Conclusions: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.

Keywords: TNF; multivariate linkage analysis; pleiotropic locus; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • BCG Vaccine / administration & dosage*
  • Chi-Square Distribution
  • Child
  • Chromosomes, Human, Pair 11
  • Endemic Diseases
  • Family
  • Genetic Pleiotropy
  • Humans
  • Interferon-gamma / administration & dosage
  • Interferon-gamma Release Tests
  • Leukocytes / drug effects
  • Leukocytes / immunology*
  • Linkage Disequilibrium
  • Mycobacterium bovis / immunology*
  • Phenotype
  • Quantitative Trait Loci
  • South Africa / epidemiology
  • Tuberculosis / blood
  • Tuberculosis / epidemiology
  • Tuberculosis / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / immunology


  • BCG Vaccine
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma