4.7 Article

Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis

Journal

Publisher

AMER THORACIC SOC
DOI: 10.1164/rccm.200710-1554OC

Keywords

tuberculosis; host genetics; MC3R; Africa

Funding

  1. Medical Research Council [G0000690] Funding Source: Medline
  2. Wellcome Trust [079828, IC18CT980375] Funding Source: Medline

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Rationale: Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control. Objectives: To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility. Methods: Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa. Measurements and Main Results: Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q 13.31-33-the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis. Conclusions: These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.

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