title: Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration.
abstract: Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10(-11) for rs4733781; P = 1.0 × 10(-10) for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis-infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Curtis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Zenner
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Cuchet-Lourenço
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Changxin
authors.initials: C
authors.lastname: Wu
authors.affiliation: University College London Genetics Institute, University College London, London, UK.
authors.forename: Kitty
authors.initials: K
authors.lastname: Lo
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Mailis
authors.initials: M
authors.lastname: Maes
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Alisaac
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Stebbings
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Liliya
authors.initials: L
authors.lastname: Kopanitsa
authors.affiliation: Samara Oblast Tuberculosis Dispensary, Samara, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Ignatyeva
authors.affiliation: Robert Koch Institute, Berlin, Germany.|Imperial College London, London, UK.|Queen Mary, University of London, London, UK.
authors.forename: Yanina
authors.initials: Y
authors.lastname: Balabanova
authors.affiliation: Public Health England National Mycobacterium Reference Laboratory, London, UK.|Imperial College London, London, UK.|Queen Mary, University of London, London, UK.
authors.forename: Vladyslav
authors.initials: V
authors.lastname: Nikolayevskyy
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Ingelore
authors.initials: I
authors.lastname: Baessmann
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Thye
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany.
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.affiliation: Public Health England National Mycobacterium Reference Laboratory, London, UK.|Imperial College London, London, UK.|Queen Mary, University of London, London, UK.
authors.forename: Francis
authors.initials: F
authors.lastname: Drobniewski
authors.affiliation: University College London Genetics Institute, University College London, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
chemical_list: C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing