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 DAPK2rs11631973G 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). ATG5rs546456T 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.

Area of Genomic Medicine GENYO Centre for Genomics and Oncological Research Pfizer University of Granada Andalusian Regional Government 18016 Granada Spain

Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague 323 00 Pilsen Czech Republic

Catalan Institute of Oncology Bellvitge Biomedical Research Institute and University of Barcelona 08908 Barcelona Spain

Centre for Individualised Infection Medicine 30625 Hannover Germany

Consortium for Biomedical Research in Epidemiology and Public Health 28029 Madrid Spain

Department for Immunology and Metabolism Life and Medical Sciences Institute University of Bonn 53115 Bonn Germany

Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Nijmegen Medical Center 6525 GA Nijmegen The Netherlands

Department of Medical Oncology Complejo Hospitalario de Jaén 23007 Jaén Spain

Department of Medicine 1 Institute of Cancer Research Medical University of Vienna Borschkegasse 8a A 1090 Vienna Austria

Department of Medicine University of Granada 18016 Granada Spain

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences of the Czech Republic 142 00 Prague Czech Republic

Division of Cancer Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Cancer Epidemiology German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Division of Preventive Oncology German Cancer Research Center 69120 Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Genetic Tumour Epidemiology Group University Medical Center Hamburg Eppendorf University Cancer Center 20246 Hamburg Germany

Genomic Oncology Area GENYO Centre for Genomics and Oncological Research Pfizer University of Granada Andalusian Regional Government 18016 Granada Spain

German Cancer Consortium 69120 Heidelberg Germany

Hematology Department Virgen de las Nieves University Hospital 18012 Granada Spain

Hopp Children's Cancer Center 69120 Heidelberg Germany

ICVS 3B's PT Government Associate Laboratory Braga Guimarães Portugal

Institute of Bioinformatics International Technology Park Bangalore Karnataka 560066 India

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University 12800 Prague Czech Republic

Instituto de Biomedicina Universidad de León 24071 León Spain

Instituto de Investigación Biosanataria IBs Granada 18012 Granada Spain

Life and Health Sciences Research Institute School of Medicine University of Minho 4710 057 Braga Portugal

Manipal Academy of Higher Education Manipal Karnataka 576104 India

Network Aging Research University of Heidelberg 69115 Heidelberg Germany

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Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization