Association study of genes controlling IL-12-dependent IFN-γ immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco

J Infect Dis. 2014 Aug 15;210(4):611-8. doi: 10.1093/infdis/jiu140. Epub 2014 Mar 8.


Background: Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity.

Methods: We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population.

Results: Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression.

Conclusions: Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.

Keywords: Behcet disease; IFN-γ; IL-12; STAT4; candidate pathway; common variant; eQTL; family-based study; genetic association; pulmonary tuberculosis.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Infant
  • Interferon-gamma / genetics*
  • Interferon-gamma / immunology
  • Interleukin-12 / genetics*
  • Interleukin-12 / immunology
  • Male
  • Middle Aged
  • Morocco
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / immunology
  • Polymorphism, Single Nucleotide
  • Risk
  • STAT4 Transcription Factor / genetics*
  • STAT4 Transcription Factor / immunology
  • Tuberculosis, Pulmonary / genetics*
  • Tuberculosis, Pulmonary / immunology
  • Young Adult


  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Interleukin-12
  • Interferon-gamma