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Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts
SIMPLE SUMMARY: We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998818/ https://www.ncbi.nlm.nih.gov/pubmed/33809172 http://dx.doi.org/10.3390/cancers13061258 |
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author | Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Martin Sánchez, Vicente Da Silva Filho, Miguel Inacio Sampaio-Marques, Belém Brezina, Stefanie Butterbach, Katja ter Horst, Rob Hoffmeister, Michael Ludovico, Paula Jurado, Manuel Li, Yang Sánchez-Rovira, Pedro Netea, Mihai G. Gsur, Andrea Vodička, Pavel Moreno, Víctor Hemminki, Kari Brenner, Hermann Chang-Claude, Jenny Försti, Asta |
author_facet | Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Martin Sánchez, Vicente Da Silva Filho, Miguel Inacio Sampaio-Marques, Belém Brezina, Stefanie Butterbach, Katja ter Horst, Rob Hoffmeister, Michael Ludovico, Paula Jurado, Manuel Li, Yang Sánchez-Rovira, Pedro Netea, Mihai G. Gsur, Andrea Vodička, Pavel Moreno, Víctor Hemminki, Kari Brenner, Hermann Chang-Claude, Jenny Försti, Asta |
author_sort | Sainz, Juan |
collection | PubMed |
description | SIMPLE SUMMARY: We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated with CRC risk. This study also shed some light onto the functional mechanisms behind the observed associations and demonstrated the impact of DAPK2(rs11631973) and ATG5(rs546456) polymorphisms on the modulation of host immune responses, blood derived-cell counts and serum inflammatory protein levels, which might be involved in promoting cancer development. No effect of the DAPK2 and ATG5 polymorphisms on the autophagy flux was observed. ABSTRACT: 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, DAPK2 (p = 2.19 × 10(−5)) and ATG5 (p = 6.28 × 10(−4)) were associated with the risk of CRC. Mechanistically, the DAPK2(rs11631973G) allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5(rs546456T) allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses. |
format | Online Article Text |
id | pubmed-7998818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79988182021-03-28 Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Martin Sánchez, Vicente Da Silva Filho, Miguel Inacio Sampaio-Marques, Belém Brezina, Stefanie Butterbach, Katja ter Horst, Rob Hoffmeister, Michael Ludovico, Paula Jurado, Manuel Li, Yang Sánchez-Rovira, Pedro Netea, Mihai G. Gsur, Andrea Vodička, Pavel Moreno, Víctor Hemminki, Kari Brenner, Hermann Chang-Claude, Jenny Försti, Asta Cancers (Basel) Article SIMPLE SUMMARY: We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated with CRC risk. This study also shed some light onto the functional mechanisms behind the observed associations and demonstrated the impact of DAPK2(rs11631973) and ATG5(rs546456) polymorphisms on the modulation of host immune responses, blood derived-cell counts and serum inflammatory protein levels, which might be involved in promoting cancer development. No effect of the DAPK2 and ATG5 polymorphisms on the autophagy flux was observed. ABSTRACT: 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, DAPK2 (p = 2.19 × 10(−5)) and ATG5 (p = 6.28 × 10(−4)) were associated with the risk of CRC. Mechanistically, the DAPK2(rs11631973G) allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5(rs546456T) allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses. MDPI 2021-03-12 /pmc/articles/PMC7998818/ /pubmed/33809172 http://dx.doi.org/10.3390/cancers13061258 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sainz, Juan García-Verdejo, Francisco José Martínez-Bueno, Manuel Kumar, Abhishek Sánchez-Maldonado, José Manuel Díez-Villanueva, Anna Vodičková, Ludmila Vymetálková, Veronika Martin Sánchez, Vicente Da Silva Filho, Miguel Inacio Sampaio-Marques, Belém Brezina, Stefanie Butterbach, Katja ter Horst, Rob Hoffmeister, Michael Ludovico, Paula Jurado, Manuel Li, Yang Sánchez-Rovira, Pedro Netea, Mihai G. Gsur, Andrea Vodička, Pavel Moreno, Víctor Hemminki, Kari Brenner, Hermann Chang-Claude, Jenny Försti, Asta 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 |
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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998818/ https://www.ncbi.nlm.nih.gov/pubmed/33809172 http://dx.doi.org/10.3390/cancers13061258 |
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