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

Graham S. Cooke^1,2,3, Sarah J. Campbell¹, Steve Bennett^4,, Christian Lienhardt⁵, Keith P. W. J. McAdam⁶, Giorgio Sirugo⁶, Oumou Sow⁷, Per Gustafson⁸, Frank Mwangulu^9,, Paul van Helden¹⁰, Paul Fine⁹, Eileen G. Hoal¹⁰ and Adrian V. S. Hill¹

¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom; ² Imperial College, London, United Kingdom; ³ Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Somkhele, South Africa; ⁴ London School of Hygiene and Tropical Medicine, London, United Kingdom; ⁵ National TB/Leprosy Control Programme, Banjul, The Gambia; ⁶ Medical Research Council Laboratories, Fajara, The Gambia; ⁷ CHU Ignace Deen, Conakry, Guinea; ⁸ Danish Epidemiology Science Centre, Bissau, Guinea-Bissau; ⁹ Karonga Prevention Study, Chilumba, Malawi; and ¹⁰ Medical Research Council Centre for Molecular and Cellular Biology, Stellenbosch University, South Africa

Correspondence and requests for reprints should be addressed to Graham S. Cooke, Ph.D., M.R.C.P., Africa Centre for Health and Population Studies, PO Box 198, Mtubatuba 3935, Somkhele, KwaZulu-Natal, South Africa. 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 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.

Key Words: tuberculosis • host genetics • MC3R • Africa

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Using prior knowledge of a gene's function, a limited number of genes have shown convincing evidence of influencing susceptibility to tuberculosis. However, new genomewide approaches can identify novel susceptibility genes with no prior knowledge of function. What This Study Adds to the Field Using a genomewide approach and positional mapping, this study identifies two novel genes, melanocortin 3 receptor and cathepsin 7, that play a role in susceptibility to tuberculosis in African populations. Both are related to macrophage function and are potential therapeutic targets.

 

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				E. Abraham Erratum: Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis Am. J. Respir. Crit. Care Med., April 1, 2009; 179(7): 624 - 624. [Full Text] [PDF]

				W. W. Yew and C. C. Leung Update in Tuberculosis 2008 Am. J. Respir. Crit. Care Med., March 1, 2009; 179(5): 337 - 343. [Full Text] [PDF]