Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts
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 t...
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/6/1258 |
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| author | Juan Sainz Francisco José García-Verdejo Manuel Martínez-Bueno Abhishek Kumar José Manuel Sánchez-Maldonado Anna Díez-Villanueva Ludmila Vodičková Veronika Vymetálková Vicente Martin Sánchez Miguel Inacio Da Silva Filho Belém Sampaio-Marques Stefanie Brezina Katja Butterbach Rob ter Horst Michael Hoffmeister Paula Ludovico Manuel Jurado Yang Li Pedro Sánchez-Rovira Mihai G. Netea Andrea Gsur Pavel Vodička Víctor Moreno Kari Hemminki Hermann Brenner Jenny Chang-Claude Asta Försti |
| author_facet | Juan Sainz Francisco José García-Verdejo Manuel Martínez-Bueno Abhishek Kumar José Manuel Sánchez-Maldonado Anna Díez-Villanueva Ludmila Vodičková Veronika Vymetálková Vicente Martin Sánchez Miguel Inacio Da Silva Filho Belém Sampaio-Marques Stefanie Brezina Katja Butterbach Rob ter Horst Michael Hoffmeister Paula Ludovico Manuel Jurado Yang Li Pedro Sánchez-Rovira Mihai G. Netea Andrea Gsur Pavel Vodička Víctor Moreno Kari Hemminki Hermann Brenner Jenny Chang-Claude Asta Försti |
| author_sort | Juan Sainz |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T13:18:23Z |
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| id | doaj.art-6b06a5a215ba4de1998a55410112d0be |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:18:23Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6b06a5a215ba4de1998a55410112d0be2023-11-21T10:15:18ZengMDPI AGCancers2072-66942021-03-01136125810.3390/cancers13061258Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large CohortsJuan Sainz0Francisco José García-Verdejo1Manuel Martínez-Bueno2Abhishek Kumar3José Manuel Sánchez-Maldonado4Anna Díez-Villanueva5Ludmila Vodičková6Veronika Vymetálková7Vicente Martin Sánchez8Miguel Inacio Da Silva Filho9Belém Sampaio-Marques10Stefanie Brezina11Katja Butterbach12Rob ter Horst13Michael Hoffmeister14Paula Ludovico15Manuel Jurado16Yang Li17Pedro Sánchez-Rovira18Mihai G. Netea19Andrea Gsur20Pavel Vodička21Víctor Moreno22Kari Hemminki23Hermann Brenner24Jenny Chang-Claude25Asta Försti26Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, SpainDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainArea of Genomic Medicine, GENYO, Centre for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, SpainDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, SpainCatalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and University of Barcelona, 08908 Barcelona, SpainDepartment of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 00 Prague, Czech RepublicDepartment of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 00 Prague, Czech RepublicConsortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, SpainDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, PortugalDepartment of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, AustriaNetwork Aging Research (NAR), University of Heidelberg, 69115 Heidelberg, GermanyDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, PortugalGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, SpainDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, AustriaDepartment of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 00 Prague, Czech RepublicCatalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and University of Barcelona, 08908 Barcelona, SpainDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyNetwork Aging Research (NAR), University of Heidelberg, 69115 Heidelberg, GermanyDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyThe 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.https://www.mdpi.com/2072-6694/13/6/1258colorectal cancerautophagygenetic variantssusceptibility |
| spellingShingle | Juan Sainz Francisco José García-Verdejo Manuel Martínez-Bueno Abhishek Kumar José Manuel Sánchez-Maldonado Anna Díez-Villanueva Ludmila Vodičková Veronika Vymetálková Vicente Martin Sánchez Miguel Inacio Da Silva Filho Belém Sampaio-Marques Stefanie Brezina Katja Butterbach Rob ter Horst Michael Hoffmeister Paula Ludovico Manuel Jurado Yang Li Pedro Sánchez-Rovira Mihai G. Netea Andrea Gsur Pavel Vodička Víctor Moreno Kari Hemminki Hermann Brenner Jenny Chang-Claude Asta Försti Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts Cancers colorectal cancer autophagy genetic variants susceptibility |
| 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 | colorectal cancer autophagy genetic variants susceptibility |
| url | https://www.mdpi.com/2072-6694/13/6/1258 |
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