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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region
American Journal of Human Genetics, Volume 92, No. 3, Year 2013
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Description
Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12-13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10-5 and 9.2 × 10-5, respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10-8; odds ratio of PTB for AA versus AG/GG = 3.09 [1.99-4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3′ region of TOX, and further functional explorations will focus on CD4 T lymphocytes. © 2013 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3591857/bin/mmc1.pdf
Authors & Co-Authors
Grant, Audrey Virginia
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
El-Baghdadi, Jamila
Morocco, Agdal Rabat
Military Hospital Mohammed V
Sabri, Ayoub
Morocco, Agdal Rabat
Military Hospital Mohammed V
El Azbaoui, Safa
Morocco, Agdal Rabat
Military Hospital Mohammed V
Alaoui-Tahiri, Kebir
Morocco, Agdal Rabat
Military Hospital Mohammed V
Abderrahmani-Rhorfi, Ismail
Morocco, Agdal Rabat
Military Hospital Mohammed V
Gharbaoui, Yasser
Morocco, Agdal Rabat
Military Hospital Mohammed V
Abid, Ahmed
Morocco, Agdal Rabat
Military Hospital Mohammed V
Benkirane, Majid
Morocco, Agdal Rabat
Military Hospital Mohammed V
Raharimanga, Vaomalala
Madagascar, Antananarivo
Institut Pasteur de Madagascar
Richard, Vincent
Madagascar, Antananarivo
Institut Pasteur de Madagascar
Orlova, Marianna O.
Canada, Montreal
Centre Universitaire de Santé Mcgill
Boland, Anne
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Migaud, Mélanie
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
Okada, Satoshi
United States, New York
Rockefeller University
Nolan, Daniel
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
Bustamante, Jacinta Cecilia
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
France, Paris
Hôpital Necker Enfants Malades
Barreiro, Luis B.
Canada, Montreal
University of Montreal
Schurr, Erwin
Canada, Montreal
Centre Universitaire de Santé Mcgill
Boisson-Dupuis, Stéphanie
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
United States, New York
Rockefeller University
Rasolofo-Razanamparany, Voahangy
Madagascar, Antananarivo
Institut Pasteur de Madagascar
Casanova, Jean Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
United States, New York
Rockefeller University
France, Paris
Hôpital Necker Enfants Malades
Abel, Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Université Paris Cité
United States, New York
Rockefeller University
Statistics
Citations: 48
Authors: 23
Affiliations: 9
Identifiers
Doi:
10.1016/j.ajhg.2013.01.013
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases
Study Design
Case-Control Study
Study Locations
Madagascar
Morocco