A functional haplotype in the 3'untranslated region of TNFRSF1B is associated with tuberculosis in two African populations.

Abstract

RATIONALE:

Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. The pleiotropic cytokine tumor necrosis factor-alpha is essential to control tuberculosis infection, and various tumor necrosis factor family members and their respective receptors may contribute to tuberculosis risk.

OBJECTIVES:

To investigate four functionally relevant polymorphisms in the tumor necrosis factor receptor 2-encoding gene, tumor necrosis factor receptor superfamily member 1B, for association with tuberculosis susceptibility.

METHODS:

Genotyping of four polymorphisms was performed in independent populations from South Africa (429 cases and 482 control subjects) and Ghana (640 cases and 1,158 control subjects), and the association of the variants with tuberculosis was tested using two case-control association studies.

MEASUREMENTS AND MAIN RESULTS:

Single-point and haplotype analysis in South Africans revealed an association in the 3'untranslated region of the investigated gene. The T allele of rs3397 alone and/or the 3' untranslated region haplotype GTT may confer protection against tuberculosis insofar as both allele and haplotype frequencies were significantly lower in case subjects than in controls. The GTT genotype had previously been shown to increase the decay of tumor necrosis factor receptor 2 messenger ribonucleic acid, and messenger ribonucleic acid destabilization may represent a key molecular mechanism for disease susceptibility. Interestingly, the association signal appeared to be restricted to women. The genetic finding was validated in female participants from Ghana. The combined P value in the haplotype analysis was P = 0.00011.

CONCLUSIONS:

Our finding emphasizes the importance of tumor necrosis factor/tumor necrosis factor receptor-mediated immune responses in the pathogenesis of tuberculosis.

• Authors: Marlo Möller, Friederike Flachsbart, Andreas Till, Thorsten Thye, Rolf D Horstmann, Christian G Meyer, Ivy Osei, Paul D van Helden, Eileen G Hoal, Stefan Schreiber, Almut Nebel, Andre Franke
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 181 Issue 4 Pg. 388-93 (Feb 15 2010) ISSN: 1535-4970 [Electronic] United States
• PMID: 20007930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Receptors, Tumor Necrosis Factor, Type II
• TNFRSF1B protein, human

Topics

• 3' Untranslated Regions (genetics)
• Alleles
• Black People (genetics)
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease (genetics)
• Genotype
• Ghana
• Haplotypes (genetics)
• Humans
• Male
• Polymorphism, Single Nucleotide (genetics)
• Receptors, Tumor Necrosis Factor, Type II (genetics)
• Sex Factors
• South Africa
• Tuberculosis, Pulmonary (genetics)