title: Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.
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.
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.
authors: Audrey V
authors: AV
authors: Grant
authors: Jamila
authors: J
authors: El Baghdadi
authors: Ayoub
authors: A
authors: Sabri
authors: Safa
authors: S
authors: El Azbaoui
authors: Kebir
authors: K
authors: Alaoui-Tahiri
authors: Ismail
authors: I
authors: Abderrahmani Rhorfi
authors: Yasser
authors: Y
authors: Gharbaoui
authors: Ahmed
authors: A
authors: Abid
authors: Majid
authors: M
authors: Benkirane
authors: Vaomalala
authors: V
authors: Raharimanga
authors: Vincent
authors: V
authors: Richard
authors: Marianna
authors: M
authors: Orlova
authors: Anne
authors: A
authors: Boland
authors: Mélanie
authors: M
authors: Migaud
authors: Satoshi
authors: S
authors: Okada
authors: Daniel K
authors: DK
authors: Nolan
authors: Jacinta
authors: J
authors: Bustamante
authors: Luis B
authors: LB
authors: Barreiro
authors: Erwin
authors: E
authors: Schurr
authors: Stephanie
authors: S
authors: Boisson-Dupuis
authors: Voahangy
authors: V
authors: Rasolofo
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Laurent
authors: L
authors: Abel
mesh_terms: D000328:Adult; D000367:Age Factors; D000483:Alleles; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008270:Madagascar; D008297:Male; D009018:Morocco; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000382:microbiology; D044465:White People
chemical_list: D006609:High Mobility Group Proteins; C558851:TOX protein, human