Published ahead of print on April 17, 2008, doi:10.1164/rccm.200710-1554OC Am. J. Respir. Crit. Care Med., Volume 178, Number 2, July 2008, 203-207 A more recent version of this article appeared on July 15, 2008
Submitted on October 22, 2007 Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human TuberculosisGraham S Cooke1*,1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Imperial College, London, United Kingdom; Africa Centre for Health and Population Studies UKZN, Somkhele, South Africa, 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 3 London School of Hygiene and Tropical Medicine, London, United Kingdom, 4 Medical Research Council Laboratories, Fajara, Gambia, 5 CHU Ignace Deen, Conakry, Guinea, 6 Danish Epidemiology Science Centre, Bissau, Guinea-Bissau, 7 Karonga Prevention Study, Chilumba, Malawi, 8 MRC Centre for Molecular and Cellular Biology, Stellenbosch University, Stellenbosch, South Africa * To whom correspondence should be addressed. E-mail: gcooke{at}africacentre.ac.za.
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 MLS of 2.8). An independent, multi-stage 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 genome-wide approach to the complex phenotype of human tuberculosis can identify novel targets for further research. Key words: tuberculosis, host genetics, MC3R, Africa
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