title: Association study of genes controlling IL-12-dependent IFN-γ immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco.
abstract: BACKGROUND
  Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity.
  
  
  METHODS
  We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population.
  
  
  RESULTS
  Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression.
  
  
  CONCLUSIONS
  Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.
authors.affiliation: Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco Faculty of Science-Kenitra, Ibn Tofail University, Kenitra, Morocco.
authors.forename: Ayoub
authors.initials: A
authors.lastname: Sabri
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Audrey V
authors.initials: AV
authors.lastname: Grant
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Kristel
authors.initials: K
authors.lastname: Cosker
authors.affiliation: Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco Faculty of Science-Kenitra, Ibn Tofail University, Kenitra, Morocco.
authors.forename: Safa
authors.initials: S
authors.lastname: El Azbaoui
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abid
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Ismail
authors.initials: I
authors.lastname: Abderrahmani Rhorfi
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Hicham
authors.initials: H
authors.lastname: Souhi
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Hicham
authors.initials: H
authors.lastname: Janah
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Kebir
authors.initials: K
authors.lastname: Alaoui-Tahiri
authors.affiliation: Department of Pneumology, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Gharbaoui
authors.affiliation: Blood Transfusion Center, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Majid
authors.initials: M
authors.lastname: Benkirane
authors.affiliation: McGill International TB Centre, The Research Institute of the McGill University Health Centre, Montreal, Canada.
authors.forename: Marianna
authors.initials: M
authors.lastname: Orlova
authors.affiliation: CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Anne
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, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Caroline
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, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Migaud
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France Center for the Study of Primary Immunodeficiencies, AP-HP, Necker hospital, Paris France.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: McGill International TB Centre, The Research Institute of the McGill University Health Centre, Montreal, Canada.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
authors.forename: Stephanie
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, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital, Paris, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Jamila
authors.initials: J
authors.lastname: El Baghdadi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009018:Morocco; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Behcet disease; IFN-γ; IL-12; STAT4; candidate pathway; common variant; eQTL; family-based study; genetic association; pulmonary tuberculosis