This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200905-0678OCv1 181/4/388    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Möller, M. Articles by Franke, A. PubMed PubMed Citation Articles by Möller, M. Articles by Franke, A.

A Functional Haplotype in the 3'Untranslated Region of TNFRSF1B Is Associated with Tuberculosis in Two African Populations

¹ Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa; ² Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; ³ Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; and ⁴ Health Research Unit, Ghana Health Service, Accra, Ghana

Correspondence and requests for reprints should be addressed to Andre Franke, Ph.D., Institute of Clinical Molecular Biology, Christian-Albrechts-University, Arnold-Heller-Straße 3, 24105 Kiel, Germany. E-mail: a.franke{at}mucosa.de

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- 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.

Key Words: Mycobacterium tuberculosis • genetic susceptibility • association study

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, is estimated to result in more than 2 million deaths annually, mostly in developing countries. There is growing evidence that genetic variation in the human host also plays an important role in resistance or susceptibility to the disease. What This Study Adds to the Field This study provides evidence that variation in the 3'untranslated region of the tumor necrosis factor receptor superfamily member 1B gene, which has been shown to be implicated in messenger ribonucleic acid destabilization, contributes to tuberculosis susceptibility.