Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

Alfred Sokolowski Specialist Hospital in Walbrzych Oncology Support Centre for Clinical Trials 58 309 Walbrzych Poland

Cancer Control Research BC Cancer Vancouver BC V5Z 4E6 Canada

Cancer Epidemiology Division Cancer Council Victoria Melbourne VIC 3004 Australia

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences 1090 Vienna Austria

Centre for Epidemiology and Biostatistics School of Population and Global Health The University of Melbourne Melbourne VIC 3010 Australia

Centre for Individualised Infection Medicine 30625 Hannover Germany

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

Department of Biochemistry and Molecular Biology 1 University of Granada 18071 Granada Spain

Department of Biology University of Pisa 56126 Pisa Italy

Department of Biostatistics and Epidemiology Arnold School of Public Health University of South Carolina Greenville SC 29208 USA

Department of Cancer Prevention and Therapy Wroclaw Medical University 50 367 Wroclaw Poland

Department of Hematology and Transplantology Medical University of Gdansk 80 210 Gdansk Poland

Department of Hematology Experimental Hematology Unit Vall d'Hebron Institute of Oncology University Hospital Vall d'Hebron 08035 Barcelona Spain

Department of Hematology Hospital del Mar 08003 Barcelona Spain

Department of Hematology Institute of Medical Sciences College of Medical Sciences University of Rzeszow 35 310 Rzeszow Poland

Department of Hematology Medical University of Lodz 90 419 Lodz Poland

Department of Hematology Military Institute of Medicine 04 141 Warsaw Poland

Department of Hematology Odense University Hospital DK 5000 Odense Denmark

Department of Hematology Rigshospitalet Copenhagen University DK 2100 Copenhagen Denmark

Department of Hematology Rydygier Hospital 31 826 Cracow Poland

Department of Hematology Specialist Hospital No 1 in Bytom Academy of Silesia Faculty of Medicine 40 055 Katowice Poland

Department of Hematology Transplantology and Internal Medicine Medical University of Warsaw 02 097 Warsaw Poland

Department of Hematology University Hospital 30 688 Kraków Poland

Department of Hematology University Hospital No 2 85 168 Bydgoszcz Poland

Department of Hematooncology and Bone Marrow Transplantation Medical University of Lublin 20 059 Lublin Poland

Department of Internal Diseases Occupational Medicine Hypertension and Clinical Oncology Wroclaw Medical University 50 368 Wroclaw Poland

Department of Internal Medicine 5 University of Heidelberg 69120 Heidelberg Germany

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

Department of Lymphoma Myeloma Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Department of Lymphoproliferative Diseases Maria Skłodowska Curie National Research Institute of Oncology 02 781 Warsaw Poland

Department of Medical Oncology Complejo Hospitalario de Jaén 23007 Jaén Spain

Department of Medicine University of California San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco CA 94143 USA

Department of Medicine University of Granada 18012 Granada Spain

Department of Pathology Heersink School of Medicine The University of Alabama at Birmingham Birmingham AL 35294 USA

Diagnostic Laboratory Unit in Hematology University Hospital of Salamanca IBSAL CIBERONC Centro de Investigación del Cáncer IBMCC 37007 Salamanca Spain

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

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

Division of Epidemiology Department of Health Sciences Research Mayo Clinic Rochester MN 55902 USA

Division of Hematology Department of Internal Medicine Mayo Clinic Rochester MN 55902 USA

Division of Hematology Huntsman Cancer Institute University of Utah Salt Lake City UT 84112 USA

Division of Hematology Oncology Department of Medicine School of Medicine Department of Pathology School of Medicine Susan and Henry Samueli College of Health Sciences Chao Family Comprehensive Cancer Center University of California at Irvine Irvine CA 92697 USA

Division of Molecular Genetic Epidemiology German Cancer Research Center Im Neuenheimer Feld 580 D 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Division of Population Oncology BC Cancer Vancouver BC V5Z 4E6 Canada

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

Genetic Epidemiology and Risk Assessment Program Mayo Clinic Comprehensive Cancer Center Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester MN 55902 USA

Genomic Epidemiology Group German Cancer Research Center 69120 Heidelberg Germany

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

Haematology Unit Department of Clinical and Experimental Medicine University of Pisa AOUP 56126 Pisa Italy

Hematology Department Virgen de las Nieves University Hospital 18012 Granada Spain

Hematology Division Chaim Sheba Medical Center Tel Hashomer 52621 Israel

Holycross Medical Oncology Center 25 735 Kielce Poland

Hopp Children's Cancer Center 69120 Heidelberg Germany

Hospital 12 de Octubre Complutense University CNIO CIBERONC 28041 Madrid Spain

Institute of Bioinformatics International Technology Park Bangalore 560066 India

Institute of Hematology and Transfusion Medicine 00 791 Warsaw Poland

Instituto de Investigación Biosanataria IBs Granada 18014 Granada Spain

Life and Health Sciences Research Institute School of Health Sciences University of Minho 4710 057 Braga Portugal and ICVS 3B's PT Government Associate Laboratory 4710 057 Braga Guimarães Portugal

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

Manipal Academy of Higher Education Manipal 576104 India

Molecular Diagnostics and Clinical Research Unit Institute of Regional Health Research University Hospital of Southern Denmark DK 6200 Aabenraa Denmark

Molecular Oncology Research Center Barretos Cancer Hospital Barretos 14784 400 Brazil

Myeloma Institute University of Arkansas for Medical Sciences Little Rock AR 72205 USA

National Research Centre for the Working Environment DK 2100 Copenhagen Denmark

Plasma Cell Dyscrasias Center Department of Hematology Jagiellonian University Medical College 31 066 Kraków Poland

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC 3168 Australia

Program in Epidemiology Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA

School of Population and Public Health University of British Columbia Vancouver BC V6T 1Z4 Canada

Semmelweis University 1083 Budapest Hungary

St Johns Hospital 62769 Budapest Hungary

U O Dipartimento di Ematologia Azienda USL Toscana Nord Ovest 57124 Livorno Italy

UMR INSERM 1052 CNRS 5286 University of Lyon Hospices Civils de Lyon 69008 Lyon France

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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