Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis

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Abstract
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 20q13.31—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.