Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.
Cooke, Graham S;
Campbell, Sarah J;
Bennett, Steve;
Lienhardt, Christian;
McAdam, Keith PWJ;
Sirugo, Giorgio;
Sow, Oumou;
Gustafson, Per;
Mwangulu, Frank;
van Helden, Paul;
+3 more...Fine, Paul;
Hoal, Eileen G;
Hill, Adrian VS;
(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: https://doi.org/10.1164/rccm.200710-1554OC
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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.