Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. - Archive ouverte HAL Access content directly
Journal Articles American Journal of Human Genetics Year : 2013

Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.

(1, 2) , (3) , (3) , (3) , (4) , (4) , (4) , (4) , (5) , (6) , (6) , (7) , (8) , (1, 2) , (9) , (1, 2) , (1, 10) , (11) , (7) , (1, 9) , (6) , (1, 2, 9, 12) , (1, 2, 9, 13)
1
2
3
4
5
6
7
8
9
10
11
12
13
Jamila El Baghdadi
  • Function : Correspondent author
  • PersonId : 949667

Connectez-vous pour contacter l'auteur
Ayoub Sabri
  • Function : Author
Safa El Azbaoui
  • Function : Author
Anne Boland

Abstract

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.
Embargoed file
Embargoed file
Ne sera jamais visible
Loading...

Dates and versions

pasteur-00878595 , version 1 (30-10-2013)

Identifiers

Cite

Audrey V Grant, Jamila El Baghdadi, Ayoub Sabri, Safa El Azbaoui, Kebir Alaoui-Tahiri, et al.. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.. American Journal of Human Genetics, 2013, 92 (3), pp.407-14. ⟨10.1016/j.ajhg.2013.01.013⟩. ⟨pasteur-00878595⟩
279 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More