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


Cooke, GS; Campbell, SJ; Bennett, S; Lienhardt, C; McAdam, K; Sirugo, G; Sow, O; Gustafson, P; Mwangulu, F; van Helden, P; Fine, P; Hoal, EG; Hill, AVS; (2008) Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. American journal of respiratory and critical care medicine, 178 (2). pp. 203-207. ISSN 1073-449X DOI: 10.1164/rccm.200710-1554OC

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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.

Item Type: Article
Keywords: Africa, Western, epidemiology, African Continental Ancestry Group, genetics, Case-Control Studies, Cathepsins, genetics, Genetic Predisposition to Disease, ethnology, genetics, Humans, Likelihood Functions, Linkage (Genetics), Malawi, epidemiology, Microsatellite Repeats, Pedigree, Polymorphism, Genetic, Receptor, Melanocortin, Type 3, genetics, Regression Analysis, Siblings, South Africa, epidemiology, Tuberculosis, Pulmonary, ethnology, genetics
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Public Health and Policy > Dept of Global Health and Development
Research Centre: TB Centre
PubMed ID: 18420963
Web of Science ID: 257734400013
URI: http://researchonline.lshtm.ac.uk/id/eprint/7241

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