Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans
Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-base...
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| description | Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p |
| doi_str_mv | 10.1371/journal.pone.0021920 |
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Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021920</identifier><identifier>PMID: 21755009</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>African Americans ; Analysis ; Antineoplastic Agents - pharmacology ; Biology ; Black or African American - genetics ; Cancer ; Carboplatin ; Carboplatin - pharmacology ; Cell Death - drug effects ; Cell Line ; Chemotherapy ; Child ; Cisplatin ; Cisplatin - pharmacology ; Cytarabine ; Cytotoxicity ; Disease susceptibility ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Female ; Gene expression ; Genealogy and Heraldry ; Genes ; Genetic aspects ; Genetics ; Genome, Human - genetics ; Genome-Wide Association Study ; Genomes ; Genomics ; Growth rate ; Gynecology ; Haplotypes ; Hematology ; Humans ; Lymphoblastoid cell lines ; Male ; Medical research ; Medicine ; Minority & ethnic groups ; Oncology ; Phenotype ; Polymorphism, Single Nucleotide - genetics ; Population structure ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Southwestern United States ; Studies ; Toxicity ; Tumorigenesis</subject><ispartof>PloS one, 2011-07, Vol.6 (7), p.e21920</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Wheeler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Wheeler et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-2ce5376f1ea85a3816f8415982f8b958d61a2c25fdf134ce621fde4e7172ed6a3</citedby><cites>FETCH-LOGICAL-c691t-2ce5376f1ea85a3816f8415982f8b958d61a2c25fdf134ce621fde4e7172ed6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130766/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130766/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21755009$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Veitia, Reiner Albert</contributor><creatorcontrib>Wheeler, Heather E</creatorcontrib><creatorcontrib>Gorsic, Lidija K</creatorcontrib><creatorcontrib>Welsh, Marleen</creatorcontrib><creatorcontrib>Stark, Amy L</creatorcontrib><creatorcontrib>Gamazon, Eric R</creatorcontrib><creatorcontrib>Cox, Nancy J</creatorcontrib><creatorcontrib>Dolan, M Eileen</creatorcontrib><title>Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. 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Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. 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Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21755009</pmid><doi>10.1371/journal.pone.0021920</doi><tpages>e21920</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | African Americans Analysis Antineoplastic Agents - pharmacology Biology Black or African American - genetics Cancer Carboplatin Carboplatin - pharmacology Cell Death - drug effects Cell Line Chemotherapy Child Cisplatin Cisplatin - pharmacology Cytarabine Cytotoxicity Disease susceptibility Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Female Gene expression Genealogy and Heraldry Genes Genetic aspects Genetics Genome, Human - genetics Genome-Wide Association Study Genomes Genomics Growth rate Gynecology Haplotypes Hematology Humans Lymphoblastoid cell lines Male Medical research Medicine Minority & ethnic groups Oncology Phenotype Polymorphism, Single Nucleotide - genetics Population structure Single nucleotide polymorphisms Single-nucleotide polymorphism Southwestern United States Studies Toxicity Tumorigenesis |
| title | Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T03%3A14%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20local%20ancestry%20approach%20identifies%20genes%20and%20variants%20associated%20with%20chemotherapeutic%20susceptibility%20in%20African%20Americans&rft.jtitle=PloS%20one&rft.au=Wheeler,%20Heather%20E&rft.date=2011-07-06&rft.volume=6&rft.issue=7&rft.spage=e21920&rft.pages=e21920-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0021920&rft_dat=%3Cgale_plos_%3EA476886346%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1305099206&rft_id=info:pmid/21755009&rft_galeid=A476886346&rft_doaj_id=oai_doaj_org_article_ffe6859f30e64a0eb70be25a841a6a2e&rfr_iscdi=true |