Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/72715 |
Resumo: | The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, <i>DAPK2</i> (<i>p</i> = 2.19 × 10<sup>−5</sup>) and <i>ATG5</i> (<i>p</i> = 6.28 × 10<sup>−4</sup>) were associated with the risk of CRC. Mechanistically, the <i>DAPK2</i><sub>rs11631973G</sub> allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with <i>Staphylococcus aureus</i> (<i>p</i> = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (<i>p</i> = 0.0038) and serum levels of en-RAGE (<i>p</i> = 0.0068). <i>ATG5</i><sub>rs546456T</sub> allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (<i>p</i> = 0.0088 and <i>p</i> = 0.0076, respectively), CD14+CD16− cell levels in blood (<i>p</i> = 0.0068) and serum levels of CCL19 and cortisol (<i>p</i> = 0.0052 and <i>p</i> = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the <i>DAPK2</i> and <i>ATG5</i> loci in the pathogenesis of CRC, likely through the modulation of host immune responses. |
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Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohortsColorectal cancerAutophagyGenetic variantsSusceptibilityScience & TechnologyThe role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, <i>DAPK2</i> (<i>p</i> = 2.19 × 10<sup>−5</sup>) and <i>ATG5</i> (<i>p</i> = 6.28 × 10<sup>−4</sup>) were associated with the risk of CRC. Mechanistically, the <i>DAPK2</i><sub>rs11631973G</sub> allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with <i>Staphylococcus aureus</i> (<i>p</i> = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (<i>p</i> = 0.0038) and serum levels of en-RAGE (<i>p</i> = 0.0068). <i>ATG5</i><sub>rs546456T</sub> allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (<i>p</i> = 0.0088 and <i>p</i> = 0.0076, respectively), CD14+CD16− cell levels in blood (<i>p</i> = 0.0068) and serum levels of CCL19 and cortisol (<i>p</i> = 0.0052 and <i>p</i> = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the <i>DAPK2</i> and <i>ATG5</i> loci in the pathogenesis of CRC, likely through the modulation of host immune responses.This work was partially supported by grants from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02256). CORSA was funded by the Austrian Research Promotion Agency (FFG) BRIDGE grant (no. 829675, to Andrea Gsur), the “Herzfelder’sche Familienstiftung” (grant to Andrea Gsur). Czech Republic CCS was funded by GACR grants (18–09709S, 19–10543S and 20–03997S), ProgresQ28/1.LF and UNCE/MED/006 grants. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). A.K. is a recipient of a Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017) from the Department of Biotechnology (DBT), Government of India (GOI). V.M. received funding from the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds–a way to build Europe–grants PI14-00613, PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE. K.H. was supported by European Union Horizon 2020 grant No. 856620. We thank the CERCA Programme, Generalitat de Catalunya for institutional support.Multidisciplinary Digital Publishing Institute (MDPI)[et al.]Universidade do MinhoSainz, JuanGarcía-Verdejo, Francisco JoséMartínez-Bueno, ManuelKumar, AbhishekSánchez-Maldonado, José ManuelDíez-Villanueva, AnnaVodičková, LudmilaVymetálková, VeronikaMarques, Maria Belém Sousa SampaioLudovico, Paula2021-03-122021-03-12T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/72715engSainz, J.; García-Verdejo, F.J.; Martínez-Bueno, M.; Kumar, A.; Sánchez-Maldonado, J.M.; Díez-Villanueva, A.; Vodičková, L.; Vymetálková, V.; Martin Sánchez, V.; Da Silva Filho, M.I.; Sampaio-Marques, B.; Brezina, S.; Butterbach, K.; ter Horst, R.; Hoffmeister, M.; Ludovico, P.; Jurado, M.; Li, Y.; Sánchez-Rovira, P.; Netea, M.G.; Gsur, A.; Vodička, P.; Moreno, V.; Hemminki, K.; Brenner, H.; Chang-Claude, J.; Försti, A. Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts. Cancers 2021, 13, 1258. https://doi.org/10.3390/cancers130612582072-669410.3390/cancers13061258https://www.mdpi.com/2072-6694/13/6/1258info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:01:40Zoai:repositorium.sdum.uminho.pt:1822/72715Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:51:37.039487Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
title |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
spellingShingle |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts Sainz, Juan Colorectal cancer Autophagy Genetic variants Susceptibility Science & Technology |
title_short |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
title_full |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
title_fullStr |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
title_full_unstemmed |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
title_sort |
Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts |
author |
Sainz, Juan |
author_facet |
Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Marques, Maria Belém Sousa Sampaio Ludovico, Paula |
author_role |
author |
author2 |
García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Marques, Maria Belém Sousa Sampaio Ludovico, Paula |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
[et al.] Universidade do Minho |
dc.contributor.author.fl_str_mv |
Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Marques, Maria Belém Sousa Sampaio Ludovico, Paula |
dc.subject.por.fl_str_mv |
Colorectal cancer Autophagy Genetic variants Susceptibility Science & Technology |
topic |
Colorectal cancer Autophagy Genetic variants Susceptibility Science & Technology |
description |
The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, <i>DAPK2</i> (<i>p</i> = 2.19 × 10<sup>−5</sup>) and <i>ATG5</i> (<i>p</i> = 6.28 × 10<sup>−4</sup>) were associated with the risk of CRC. Mechanistically, the <i>DAPK2</i><sub>rs11631973G</sub> allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with <i>Staphylococcus aureus</i> (<i>p</i> = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (<i>p</i> = 0.0038) and serum levels of en-RAGE (<i>p</i> = 0.0068). <i>ATG5</i><sub>rs546456T</sub> allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (<i>p</i> = 0.0088 and <i>p</i> = 0.0076, respectively), CD14+CD16− cell levels in blood (<i>p</i> = 0.0068) and serum levels of CCL19 and cortisol (<i>p</i> = 0.0052 and <i>p</i> = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the <i>DAPK2</i> and <i>ATG5</i> loci in the pathogenesis of CRC, likely through the modulation of host immune responses. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-03-12 2021-03-12T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/72715 |
url |
http://hdl.handle.net/1822/72715 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Sainz, J.; García-Verdejo, F.J.; Martínez-Bueno, M.; Kumar, A.; Sánchez-Maldonado, J.M.; Díez-Villanueva, A.; Vodičková, L.; Vymetálková, V.; Martin Sánchez, V.; Da Silva Filho, M.I.; Sampaio-Marques, B.; Brezina, S.; Butterbach, K.; ter Horst, R.; Hoffmeister, M.; Ludovico, P.; Jurado, M.; Li, Y.; Sánchez-Rovira, P.; Netea, M.G.; Gsur, A.; Vodička, P.; Moreno, V.; Hemminki, K.; Brenner, H.; Chang-Claude, J.; Försti, A. Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts. Cancers 2021, 13, 1258. https://doi.org/10.3390/cancers13061258 2072-6694 10.3390/cancers13061258 https://www.mdpi.com/2072-6694/13/6/1258 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799132288964886528 |