Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration
Sergey Nejentsev and colleagues identify intronic variants in ASAP1 that associate with susceptibility to tuberculosis. They show that ASAP1 is downregulated in dendritic cells infected with Mycobacterium tuberculosis , impairing their migration and matrix degradation abilities. Human genetic factor...
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| Veröffentlicht in: | Nature genetics 2015-05, Vol.47 (5), p.523-527 |
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| creator | Curtis, James Luo, Yang Zenner, Helen L Cuchet-Lourenço, Delphine Wu, Changxin Lo, Kitty Maes, Mailis Alisaac, Ali Stebbings, Emma Liu, Jimmy Z Kopanitsa, Liliya Ignatyeva, Olga Balabanova, Yanina Nikolayevskyy, Vladyslav Baessmann, Ingelore Thye, Thorsten Meyer, Christian G Nürnberg, Peter Horstmann, Rolf D Drobniewski, Francis Plagnol, Vincent Barrett, Jeffrey C Nejentsev, Sergey |
| description | Sergey Nejentsev and colleagues identify intronic variants in
ASAP1
that associate with susceptibility to tuberculosis. They show that
ASAP1
is downregulated in dendritic cells infected with
Mycobacterium tuberculosis
, impairing their migration and matrix degradation abilities.
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. |
| doi_str_mv | 10.1038/ng.3248 |
| format | Article |
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ASAP1
that associate with susceptibility to tuberculosis. They show that
ASAP1
is downregulated in dendritic cells infected with
Mycobacterium tuberculosis
, impairing their migration and matrix degradation abilities.
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.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng.3248</identifier><identifier>PMID: 25774636</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>14/1 ; 14/34 ; 14/63 ; 45/43 ; 631/208/205 ; 692/699/255/1856 ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Adult ; Agriculture ; Animal Genetics and Genomics ; Biomedical research ; Biomedicine ; Cancer Research ; Case-Control Studies ; Cell Movement ; Cells, Cultured ; Data analysis ; Datasets ; Dendritic Cells - physiology ; Deoxyribonucleic acid ; Disease ; Disease susceptibility ; DNA ; Female ; Gene Expression ; Gene Function ; Genetic aspects ; Genetic factors ; Genetic Predisposition to Disease ; Genetic testing ; Genetic variance ; Genetic variation ; Genome-Wide Association Study ; Genomes ; Health aspects ; Human Genetics ; Humans ; Identification and classification ; Infections ; Inflammatory bowel disease ; Introns ; letter ; Logistics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein Transport ; Proteins ; Risk factors ; Studies ; Tuberculosis ; Tuberculosis, Pulmonary - genetics</subject><ispartof>Nature genetics, 2015-05, Vol.47 (5), p.523-527</ispartof><rights>Springer Nature America, Inc. 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c635t-49687890901d8b31649ea874625c417aa4f0105d94fc4228def7a7c532afe1a93</citedby><cites>FETCH-LOGICAL-c635t-49687890901d8b31649ea874625c417aa4f0105d94fc4228def7a7c532afe1a93</cites><orcidid>0000-0002-5597-9215 ; 0000-0002-1152-370X ; 0000-0002-9502-0332</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ng.3248$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ng.3248$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25774636$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Curtis, James</creatorcontrib><creatorcontrib>Luo, Yang</creatorcontrib><creatorcontrib>Zenner, Helen L</creatorcontrib><creatorcontrib>Cuchet-Lourenço, Delphine</creatorcontrib><creatorcontrib>Wu, Changxin</creatorcontrib><creatorcontrib>Lo, Kitty</creatorcontrib><creatorcontrib>Maes, Mailis</creatorcontrib><creatorcontrib>Alisaac, Ali</creatorcontrib><creatorcontrib>Stebbings, Emma</creatorcontrib><creatorcontrib>Liu, Jimmy Z</creatorcontrib><creatorcontrib>Kopanitsa, Liliya</creatorcontrib><creatorcontrib>Ignatyeva, Olga</creatorcontrib><creatorcontrib>Balabanova, Yanina</creatorcontrib><creatorcontrib>Nikolayevskyy, Vladyslav</creatorcontrib><creatorcontrib>Baessmann, Ingelore</creatorcontrib><creatorcontrib>Thye, Thorsten</creatorcontrib><creatorcontrib>Meyer, Christian G</creatorcontrib><creatorcontrib>Nürnberg, Peter</creatorcontrib><creatorcontrib>Horstmann, Rolf D</creatorcontrib><creatorcontrib>Drobniewski, Francis</creatorcontrib><creatorcontrib>Plagnol, Vincent</creatorcontrib><creatorcontrib>Barrett, Jeffrey C</creatorcontrib><creatorcontrib>Nejentsev, Sergey</creatorcontrib><title>Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Sergey Nejentsev and colleagues identify intronic variants in
ASAP1
that associate with susceptibility to tuberculosis. They show that
ASAP1
is downregulated in dendritic cells infected with
Mycobacterium tuberculosis
, impairing their migration and matrix degradation abilities.
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.</description><subject>14/1</subject><subject>14/34</subject><subject>14/63</subject><subject>45/43</subject><subject>631/208/205</subject><subject>692/699/255/1856</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adult</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Biomedical research</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Case-Control Studies</subject><subject>Cell Movement</subject><subject>Cells, Cultured</subject><subject>Data analysis</subject><subject>Datasets</subject><subject>Dendritic Cells - physiology</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>Disease susceptibility</subject><subject>DNA</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Gene Function</subject><subject>Genetic aspects</subject><subject>Genetic factors</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic testing</subject><subject>Genetic variance</subject><subject>Genetic variation</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Identification and classification</subject><subject>Infections</subject><subject>Inflammatory bowel disease</subject><subject>Introns</subject><subject>letter</subject><subject>Logistics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>Risk factors</subject><subject>Studies</subject><subject>Tuberculosis</subject><subject>Tuberculosis, Pulmonary - 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genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adult</topic><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Biomedical research</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Case-Control Studies</topic><topic>Cell Movement</topic><topic>Cells, Cultured</topic><topic>Data analysis</topic><topic>Datasets</topic><topic>Dendritic Cells - physiology</topic><topic>Deoxyribonucleic acid</topic><topic>Disease</topic><topic>Disease susceptibility</topic><topic>DNA</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Gene Function</topic><topic>Genetic aspects</topic><topic>Genetic factors</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic testing</topic><topic>Genetic variance</topic><topic>Genetic variation</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Identification and classification</topic><topic>Infections</topic><topic>Inflammatory bowel disease</topic><topic>Introns</topic><topic>letter</topic><topic>Logistics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Transport</topic><topic>Proteins</topic><topic>Risk factors</topic><topic>Studies</topic><topic>Tuberculosis</topic><topic>Tuberculosis, Pulmonary - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Curtis, James</creatorcontrib><creatorcontrib>Luo, Yang</creatorcontrib><creatorcontrib>Zenner, Helen L</creatorcontrib><creatorcontrib>Cuchet-Lourenço, Delphine</creatorcontrib><creatorcontrib>Wu, Changxin</creatorcontrib><creatorcontrib>Lo, Kitty</creatorcontrib><creatorcontrib>Maes, Mailis</creatorcontrib><creatorcontrib>Alisaac, Ali</creatorcontrib><creatorcontrib>Stebbings, Emma</creatorcontrib><creatorcontrib>Liu, Jimmy Z</creatorcontrib><creatorcontrib>Kopanitsa, Liliya</creatorcontrib><creatorcontrib>Ignatyeva, Olga</creatorcontrib><creatorcontrib>Balabanova, Yanina</creatorcontrib><creatorcontrib>Nikolayevskyy, Vladyslav</creatorcontrib><creatorcontrib>Baessmann, Ingelore</creatorcontrib><creatorcontrib>Thye, Thorsten</creatorcontrib><creatorcontrib>Meyer, Christian G</creatorcontrib><creatorcontrib>Nürnberg, Peter</creatorcontrib><creatorcontrib>Horstmann, Rolf D</creatorcontrib><creatorcontrib>Drobniewski, Francis</creatorcontrib><creatorcontrib>Plagnol, Vincent</creatorcontrib><creatorcontrib>Barrett, Jeffrey C</creatorcontrib><creatorcontrib>Nejentsev, Sergey</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Curtis, James</au><au>Luo, Yang</au><au>Zenner, Helen L</au><au>Cuchet-Lourenço, Delphine</au><au>Wu, Changxin</au><au>Lo, Kitty</au><au>Maes, Mailis</au><au>Alisaac, Ali</au><au>Stebbings, Emma</au><au>Liu, Jimmy Z</au><au>Kopanitsa, Liliya</au><au>Ignatyeva, Olga</au><au>Balabanova, Yanina</au><au>Nikolayevskyy, Vladyslav</au><au>Baessmann, Ingelore</au><au>Thye, Thorsten</au><au>Meyer, Christian G</au><au>Nürnberg, Peter</au><au>Horstmann, Rolf D</au><au>Drobniewski, Francis</au><au>Plagnol, Vincent</au><au>Barrett, Jeffrey C</au><au>Nejentsev, Sergey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2015-05-01</date><risdate>2015</risdate><volume>47</volume><issue>5</issue><spage>523</spage><epage>527</epage><pages>523-527</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><abstract>Sergey Nejentsev and colleagues identify intronic variants in
ASAP1
that associate with susceptibility to tuberculosis. They show that
ASAP1
is downregulated in dendritic cells infected with
Mycobacterium tuberculosis
, impairing their migration and matrix degradation abilities.
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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>25774636</pmid><doi>10.1038/ng.3248</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-5597-9215</orcidid><orcidid>https://orcid.org/0000-0002-1152-370X</orcidid><orcidid>https://orcid.org/0000-0002-9502-0332</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2015-05, Vol.47 (5), p.523-527 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4414475 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 14/1 14/34 14/63 45/43 631/208/205 692/699/255/1856 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adult Agriculture Animal Genetics and Genomics Biomedical research Biomedicine Cancer Research Case-Control Studies Cell Movement Cells, Cultured Data analysis Datasets Dendritic Cells - physiology Deoxyribonucleic acid Disease Disease susceptibility DNA Female Gene Expression Gene Function Genetic aspects Genetic factors Genetic Predisposition to Disease Genetic testing Genetic variance Genetic variation Genome-Wide Association Study Genomes Health aspects Human Genetics Humans Identification and classification Infections Inflammatory bowel disease Introns letter Logistics Male Middle Aged Polymorphism, Single Nucleotide Protein Transport Proteins Risk factors Studies Tuberculosis Tuberculosis, Pulmonary - genetics |
| title | Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T16%3A56%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Susceptibility%20to%20tuberculosis%20is%20associated%20with%20variants%20in%20the%20ASAP1%20gene%20encoding%20a%20regulator%20of%20dendritic%20cell%20migration&rft.jtitle=Nature%20genetics&rft.au=Curtis,%20James&rft.date=2015-05-01&rft.volume=47&rft.issue=5&rft.spage=523&rft.epage=527&rft.pages=523-527&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/ng.3248&rft_dat=%3Cgale_pubme%3EA413481875%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1679874730&rft_id=info:pmid/25774636&rft_galeid=A413481875&rfr_iscdi=true |