Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis
Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control. To identify human genomic loci with evidence of linkage to tuberculosis susceptibility...
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| Veröffentlicht in: | American journal of respiratory and critical care medicine 2008-07, Vol.178 (2), p.203-207 |
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| creator | Cooke, Graham S Campbell, Sarah J Bennett, Steve Lienhardt, Christian McAdam, Keith P. W. J Sirugo, Giorgio Sow, Oumou Gustafson, Per Mwangulu, Frank van Helden, Paul Fine, Paul Hoal, Eileen G Hill, Adrian V. S |
| description | Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control.
To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.
Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.
Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.
These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research. |
| doi_str_mv | 10.1164/rccm.200710-1554OC |
| format | Article |
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To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.
Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.
Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.
These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.200710-1554OC</identifier><identifier>PMID: 18420963</identifier><language>eng</language><publisher>New York, NY: Am Thoracic Soc</publisher><subject>Africa, Western - epidemiology ; African Continental Ancestry Group - genetics ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Biological and medical sciences ; Blood coagulation. Blood cells ; Case-Control Studies ; Cathepsin K ; Cathepsin Z ; Cathepsins - genetics ; Ethics ; Fundamental and applied biological sciences. Psychology ; Gene loci ; Genetic Linkage ; Genetic Predisposition to Disease - ethnology ; Genetic Predisposition to Disease - genetics ; Genetics ; Genomes ; H. Tuberculosis ; HIV ; Human immunodeficiency virus ; Humans ; Intensive care medicine ; Likelihood Functions ; Malawi - epidemiology ; Medical research ; Medical sciences ; Microsatellite Repeats ; Molecular and cellular biology ; Pathogenesis ; Pedigree ; Platelet ; Polymorphism, Genetic ; Receptor, Melanocortin, Type 3 - genetics ; Regression Analysis ; Siblings ; South Africa - epidemiology ; Tuberculosis ; Tuberculosis, Pulmonary - ethnology ; Tuberculosis, Pulmonary - genetics</subject><ispartof>American journal of respiratory and critical care medicine, 2008-07, Vol.178 (2), p.203-207</ispartof><rights>2008 INIST-CNRS</rights><rights>Copyright American Thoracic Society Jul 15, 2008</rights><rights>Copyright © 2008, American Thoracic Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-e4c450b64b672f835ff52212ee25baf809e85bbeb255d2079c925a55240ed1d53</citedby><cites>FETCH-LOGICAL-c557t-e4c450b64b672f835ff52212ee25baf809e85bbeb255d2079c925a55240ed1d53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,4025,4026,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20498260$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18420963$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cooke, Graham S</creatorcontrib><creatorcontrib>Campbell, Sarah J</creatorcontrib><creatorcontrib>Bennett, Steve</creatorcontrib><creatorcontrib>Lienhardt, Christian</creatorcontrib><creatorcontrib>McAdam, Keith P. W. J</creatorcontrib><creatorcontrib>Sirugo, Giorgio</creatorcontrib><creatorcontrib>Sow, Oumou</creatorcontrib><creatorcontrib>Gustafson, Per</creatorcontrib><creatorcontrib>Mwangulu, Frank</creatorcontrib><creatorcontrib>van Helden, Paul</creatorcontrib><creatorcontrib>Fine, Paul</creatorcontrib><creatorcontrib>Hoal, Eileen G</creatorcontrib><creatorcontrib>Hill, Adrian V. S</creatorcontrib><title>Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control.
To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.
Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.
Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.
These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.</description><subject>Africa, Western - epidemiology</subject><subject>African Continental Ancestry Group - genetics</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Blood coagulation. Blood cells</subject><subject>Case-Control Studies</subject><subject>Cathepsin K</subject><subject>Cathepsin Z</subject><subject>Cathepsins - genetics</subject><subject>Ethics</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene loci</subject><subject>Genetic Linkage</subject><subject>Genetic Predisposition to Disease - ethnology</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genetics</subject><subject>Genomes</subject><subject>H. Tuberculosis</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Intensive care medicine</subject><subject>Likelihood Functions</subject><subject>Malawi - epidemiology</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Microsatellite Repeats</subject><subject>Molecular and cellular biology</subject><subject>Pathogenesis</subject><subject>Pedigree</subject><subject>Platelet</subject><subject>Polymorphism, Genetic</subject><subject>Receptor, Melanocortin, Type 3 - genetics</subject><subject>Regression Analysis</subject><subject>Siblings</subject><subject>South Africa - epidemiology</subject><subject>Tuberculosis</subject><subject>Tuberculosis, Pulmonary - ethnology</subject><subject>Tuberculosis, Pulmonary - genetics</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkV9r1TAYxosobk6_gBcSBAUvOpO3SdPcDKSoE84cbEcQb0Kapj05pE1N2sm-vTn0MP9cJSS_53nz5MmylwSfE1LS90Hr4Rww5gTnhDF6XT_KTgkrWE4Fx4_THvMip1R8P8mexbjHmEBF8NPshFQUsCiL00xeqWmyY498hxT66u-MQ7dL1GaabWOdne_RxuslpsO-N3GOibrxzqDOB3RVFzdIjS2qt7c_kB3R5TKoEW2XxgS9OB9tfJ496ZSL5sVxPcu-ffq4rS_zzfXnL_WHTa4Z43NuqKYMNyVtSg5dVbCuYwAEjAHWqK7CwlSsaUwDjLWAudACmGIMKDYtaVlxll2svtPSDKbVZpyDcnIKdlDhXnpl5b83o93J3t9JKGkBBCeDt0eD4H8uKakcbPoG59Ro_BJlKYBzxkkCX_8H7v0SxhROEiFKjIHxBMEK6eBjDKZ7eAnB8lCePJQn1_LkWl4Svfo7wx_Jsa0EvDkCKmrluqBGbeMDB5iKCspDlncrt7P97pcNRsZBOZdsiVT7w2TCKwlJUBS_AeoisP0</recordid><startdate>20080715</startdate><enddate>20080715</enddate><creator>Cooke, Graham S</creator><creator>Campbell, Sarah J</creator><creator>Bennett, Steve</creator><creator>Lienhardt, Christian</creator><creator>McAdam, Keith P. 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W. J</au><au>Sirugo, Giorgio</au><au>Sow, Oumou</au><au>Gustafson, Per</au><au>Mwangulu, Frank</au><au>van Helden, Paul</au><au>Fine, Paul</au><au>Hoal, Eileen G</au><au>Hill, Adrian V. S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2008-07-15</date><risdate>2008</risdate><volume>178</volume><issue>2</issue><spage>203</spage><epage>207</epage><pages>203-207</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control.
To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.
Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.
Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.
These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.</abstract><cop>New York, NY</cop><pub>Am Thoracic Soc</pub><pmid>18420963</pmid><doi>10.1164/rccm.200710-1554OC</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1073-449X |
| ispartof | American journal of respiratory and critical care medicine, 2008-07, Vol.178 (2), p.203-207 |
| issn | 1073-449X 1535-4970 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2643210 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete; American Thoracic Society (ATS) Journals Online; Alma/SFX Local Collection |
| subjects | Africa, Western - epidemiology African Continental Ancestry Group - genetics Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Biological and medical sciences Blood coagulation. Blood cells Case-Control Studies Cathepsin K Cathepsin Z Cathepsins - genetics Ethics Fundamental and applied biological sciences. Psychology Gene loci Genetic Linkage Genetic Predisposition to Disease - ethnology Genetic Predisposition to Disease - genetics Genetics Genomes H. Tuberculosis HIV Human immunodeficiency virus Humans Intensive care medicine Likelihood Functions Malawi - epidemiology Medical research Medical sciences Microsatellite Repeats Molecular and cellular biology Pathogenesis Pedigree Platelet Polymorphism, Genetic Receptor, Melanocortin, Type 3 - genetics Regression Analysis Siblings South Africa - epidemiology Tuberculosis Tuberculosis, Pulmonary - ethnology Tuberculosis, Pulmonary - genetics |
| title | Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis |
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