PMID- 25774636 OWN - NLM STAT- MEDLINE DCOM- 20150706 LR - 20230709 IS - 1546-1718 (Electronic) IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 47 IP - 5 DP - 2015 May TI - Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. PG - 523-527 LID - 10.1038/ng.3248 [doi] AB - 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 x 10(-11) for rs4733781; P = 1.0 x 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. FAU - Curtis, James AU - Curtis J AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Luo, Yang AU - Luo Y AD - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. FAU - Zenner, Helen L AU - Zenner HL AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Cuchet-Lourenco, Delphine AU - Cuchet-Lourenco D AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Wu, Changxin AU - Wu C AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Lo, Kitty AU - Lo K AD - University College London Genetics Institute, University College London, London, UK. FAU - Maes, Mailis AU - Maes M AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Alisaac, Ali AU - Alisaac A AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Stebbings, Emma AU - Stebbings E AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Liu, Jimmy Z AU - Liu JZ AD - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. FAU - Kopanitsa, Liliya AU - Kopanitsa L AD - Department of Medicine, University of Cambridge, Cambridge, UK. FAU - Ignatyeva, Olga AU - Ignatyeva O AD - Samara Oblast Tuberculosis Dispensary, Samara, Russia. FAU - Balabanova, Yanina AU - Balabanova Y AD - Robert Koch Institute, Berlin, Germany. AD - Imperial College London, London, UK. AD - Queen Mary, University of London, London, UK. FAU - Nikolayevskyy, Vladyslav AU - Nikolayevskyy V AD - Public Health England National Mycobacterium Reference Laboratory, London, UK. AD - Imperial College London, London, UK. AD - Queen Mary, University of London, London, UK. FAU - Baessmann, Ingelore AU - Baessmann I AD - Cologne Center for Genomics, University of Cologne, Cologne, Germany. FAU - Thye, Thorsten AU - Thye T AD - Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany. FAU - Meyer, Christian G AU - Meyer CG AD - Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany. FAU - Nurnberg, Peter AU - Nurnberg P AD - Cologne Center for Genomics, University of Cologne, Cologne, Germany. AD - Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. AD - Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. FAU - Horstmann, Rolf D AU - Horstmann RD AD - Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany. FAU - Drobniewski, Francis AU - Drobniewski F AD - Public Health England National Mycobacterium Reference Laboratory, London, UK. AD - Imperial College London, London, UK. AD - Queen Mary, University of London, London, UK. FAU - Plagnol, Vincent AU - Plagnol V AD - University College London Genetics Institute, University College London, London, UK. FAU - Barrett, Jeffrey C AU - Barrett JC AD - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. FAU - Nejentsev, Sergey AU - Nejentsev S AD - Department of Medicine, University of Cambridge, Cambridge, UK. LA - eng GR - 088838/Z/09/Z/WT_/Wellcome Trust/United Kingdom GR - 076113/WT_/Wellcome Trust/United Kingdom GR - 085475/WT_/Wellcome Trust/United Kingdom GR - 095198/WT_/Wellcome Trust/United Kingdom GR - 090355/WT_/Wellcome Trust/United Kingdom GR - 095198/Z/10/Z/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 088838/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150316 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 RN - 0 (ASAP1 protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) SB - IM CIN - Clin Genet. 2015 Dec;88(6):530-1. PMID: 25970765 MH - Adaptor Proteins, Signal Transducing/*genetics/metabolism MH - Adult MH - Case-Control Studies MH - Cell Movement MH - Cells, Cultured MH - Dendritic Cells/*physiology MH - Female MH - Gene Expression MH - Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - Humans MH - Introns MH - Male MH - Middle Aged MH - Polymorphism, Single Nucleotide MH - Protein Transport MH - Tuberculosis, Pulmonary/*genetics PMC - PMC4414475 MID - EMS62306 OID - NLM: EMS62306 EDAT- 2015/03/17 06:00 MHDA- 2015/07/07 06:00 PMCR- 2015/11/01 CRDT- 2015/03/17 06:00 PHST- 2014/04/19 00:00 [received] PHST- 2015/02/18 00:00 [accepted] PHST- 2015/03/17 06:00 [entrez] PHST- 2015/03/17 06:00 [pubmed] PHST- 2015/07/07 06:00 [medline] PHST- 2015/11/01 00:00 [pmc-release] AID - 10.1038/ng.3248 [doi] PST - ppublish SO - Nat Genet. 2015 May;47(5):523-527. doi: 10.1038/ng.3248. Epub 2015 Mar 16.