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


OBJECTIVE
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.


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.
Möller
Marlo
M
Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology and DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa.
Flachsbart
Friederike
F
Till
Andreas
A
Thye
Thorsten
T
Horstmann
Rolf D
RD
Meyer
Christian G
CG
Osei
Ivy
I
van Helden
Paul D
PD
Hoal
Eileen G
EG
Schreiber
Stefan
S
Nebel
Almut
A
Franke
Andre
A
D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D044383:Black People / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D005869:Ghana; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D012737:Sex Factors; D013019:South Africa; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
D020413:3' Untranslated Regions; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human