title: A genome-wide association study of pulmonary tuberculosis in Morocco.
abstract: Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10(-4). The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10(-6) < p < 4 × 10(-5)): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10(-6)) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.
authors.forename: A V
authors.initials: AV
authors.lastname: Grant
authors.affiliation: Genetics Unit, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.|Faculty of Sciences-Kenitra, Ibn Tofail University, Kenitra, Morocco.
authors.forename: A
authors.initials: A
authors.lastname: Sabri
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: A
authors.initials: A
authors.lastname: Abid
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: I
authors.initials: I
authors.lastname: Abderrahmani Rhorfi
authors.affiliation: Blood Transfusion Center, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: M
authors.initials: M
authors.lastname: Benkirane
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: H
authors.initials: H
authors.lastname: Souhi
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: H
authors.initials: H
authors.lastname: Naji Amrani
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: K
authors.initials: K
authors.lastname: Alaoui-Tahiri
authors.affiliation: Department of Pneumology, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco.
authors.forename: Y
authors.initials: Y
authors.lastname: Gharbaoui
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: F
authors.initials: F
authors.lastname: Lazrak
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: I
authors.initials: I
authors.lastname: Sentissi
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: M
authors.initials: M
authors.lastname: Manessouri
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: S
authors.initials: S
authors.lastname: Belkheiri
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: S
authors.initials: S
authors.lastname: Zaid
authors.affiliation: Centre de Diagnostic de la tuberculose et des Maladies Respiratoires [CDTMR], Salé, Morocco.
authors.forename: A
authors.initials: A
authors.lastname: Bouraqadi
authors.affiliation: National Blood Transfusion Center, Rabat, Morocco.
authors.forename: N
authors.initials: N
authors.lastname: El Amraoui
authors.affiliation: National Blood Transfusion Center, Rabat, Morocco.
authors.forename: M
authors.initials: M
authors.lastname: Hakam
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.
authors.forename: A
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: McGill Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montreal, PQ H3G 1A4, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Orlova
authors.affiliation: CEA, Institut de Génomique, Centre National de Génotypage, 91000, Evry, France, EU.
authors.forename: A
authors.initials: A
authors.lastname: Boland
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.
authors.forename: C
authors.initials: C
authors.lastname: Deswarte
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.
authors.forename: L
authors.initials: L
authors.lastname: Amar
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, 10065, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.|Center for the Study of Primary Immunodeficiencies, AP-HP, Necker hospital, 75015, Paris, France, EU.
authors.forename: S
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU.|Center for the Study of Primary Immunodeficiencies, AP-HP, Necker hospital, 75015, Paris, France, EU.|Howard Hughes Medical Institute, New York, NY, USA.|Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital, 75015, Paris, France, EU.
authors.forename: J L
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: McGill Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montreal, PQ H3G 1A4, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Schurr
authors.affiliation: Genetics Unit, Military Hospital Mohammed V, Hay Riad, 10100, Rabat, Morocco. baghdadijamila@yahoo.fr.
authors.forename: J
authors.initials: J
authors.lastname: El Baghdadi
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France, EU. laurent.abel@inserm.fr.|Paris Descartes University, Imagine Institute, 75015, Paris, France, EU. laurent.abel@inserm.fr.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, 10065, New York, NY, USA. laurent.abel@inserm.fr.|Human Genetics of Infectious Diseases, INSERM, Université Paris Descartes, Unit 1163, Imagine Institute, 24 Bd du Montparnasse, 75105, Paris, France. laurent.abel@inserm.fr.
authors.forename: L
authors.initials: L
authors.lastname: Abel
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D007223:Infant; D007438:Introns; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009018:Morocco; D009169:Mycobacterium tuberculosis; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000382:microbiology; D055815:Young Adult
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C020678:glyceryl-ether monooxygenase