The Journal of Experimental Medicine
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doi:10.1084/jem.20090892
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Cobat et al.
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BRIEF DEFINITIVE REPORT

 Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis

Aurelie Cobat1,2, Caroline J. Gallant3,4, Leah Simkin3, Gillian F. Black5, Kim Stanley5, Jane Hughes6, T. Mark Doherty7, Willem A. Hanekom6, Brian Eley8, Jean-Philippe Jaïs2, Anne Boland-Auge9, Paul van Helden5, Jean-Laurent Casanova1,2,10, Laurent Abel1,2,10, Eileen G. Hoal5, Erwin Schurr3,4, and Alexandre Alcaïs1,2,10

1 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris 75015, France
2 Necker Medical School, University Paris Descartes, Paris 75015, France
3 McGill Centre for the Study of Host Resistance, and 4 Department of Human Genetics and Department of Medicine, McGill University, Quebec H3A 2T5, Canada
5 Molecular Biology and Human Genetics, Faculty of Health Sciences, Medical Research Council Centre for Molecular and Cellular Biology, Department of Science and Technology/National Research Centre of Excellence for Biomedical TB Research, Stellenbosch University, Tygerberg 7505, South Africa
6 South African Tuberculosis Vaccine Initiative, Health Sciences Faculty, School of Child and Adolescent Health and Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
7 Statens Serum Institute, Copenhagen DK-2300, Denmark
8 Pediatric Infectious Diseases Unit, Red Cross Children's Hospital, School of Child and Adolescent Health, University of Cape Town, Cape Town 7700, South Africa
9 Centre National de Génotypage, Institut de Génomique, Commissariat à l'energie atomique, Cedex Evry 91057, France
10 Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065

CORRESPONDENCE A. Alcaïs: alexandre.alcais{at}inserm.fr OR E. Schurr: erwin.schurr{at}mcgill.ca

Approximately 20% of persons living in areas hyperendemic for tuberculosis (TB) display persistent lack of tuberculin skin test (TST) reactivity and appear to be naturally resistant to infection by Mycobacterium tuberculosis. Among those with a positive response, the intensity of TST reactivity varies greatly. The genetic basis of TST reactivity is not known. We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as zero versus nonzero (TST-BINa) or as extent of TST in millimeters (TST–quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST1) on chromosomal region 11p14 (P = 1.4 x 10–5), which controls TST-BINa, with a lack of responsiveness indicating T cell–independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10–5), which controls TST-QTL or the intensity of T cell–mediated delayed type hypersensitivity (DTH) to tuberculin. Fine mapping of this region identified SLC6A3, encoding the dopamine transporter DAT1, as a promising gene for further studies. Our results pave the way for the understanding of the molecular mechanisms involved in resistance to M. tuberculosis infection in endemic areas (TST1) and for the identification of critical regulators of T cell–dependent DTH to tuberculin (TST2).

A. Cobat and C.J. Gallant contributed equally to this paper.

E. Schurr and A. Alcaïs contributed equally to this paper.

Abbreviations used: BCG, Bacillus Calmette-Guérin; DTH, delayed type hypersensitivity; GWL, genome-wide linkage; IC, information content; LD, linkage disequilibrium; PPD, purified protein derivative; QTL, quantitative trait locus; SNP, single nucleotide polymorphism; TB, tuberculosis; TST, tuberculin skin test.

© 2009 Cobat et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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