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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 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.

Original publication




Journal article


Am J Respir Crit Care Med

Publication Date





203 - 207


Africa, Western, African Continental Ancestry Group, Case-Control Studies, Cathepsin K, Cathepsin Z, Cathepsins, Genetic Linkage, Genetic Predisposition to Disease, Humans, Likelihood Functions, Malawi, Microsatellite Repeats, Pedigree, Polymorphism, Genetic, Receptor, Melanocortin, Type 3, Regression Analysis, Siblings, South Africa, Tuberculosis, Pulmonary