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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 &lt; 1 \u00d7 10\u22129) 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 \u00d7 10\u22124\u22125.79 \u00d7 10\u221214). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 \u00d7 10\u22124), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 \u00d7 10\u22124) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 \u00d7 10\u22124). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3\u2212 B cells, CD5+IgD\u2212 cells, IgM\u2212 cells, IgD\u2212IgM\u2212 cells, and CD4\u2212CD8\u2212 PBMCs (p = 4.9 \u00d7 10\u22124\u22128.6 \u00d7 10\u22124) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27\u2212 cells (p = 9.3 \u00d7 10\u22124). 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\u2212, MCP-2\u2212, and IL20-dependent pathways.<\/jats:p>","DOI":"10.3390\/ijms24108500","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T03:32:27Z","timestamp":1683689547000},"page":"8500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization"],"prefix":"10.3390","volume":"24","author":[{"given":"Esther","family":"Clavero","sequence":"first","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-3675","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Sanchez-Maldonado","sequence":"additional","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS, 18016 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanataria IBs, Granada, 18014 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelica","family":"Macauda","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Ter Horst","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6580-0971","authenticated-orcid":false,"given":"Bel\u00e9m","family":"Sampaio-Marques","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9796-8365","authenticated-orcid":false,"given":"Artur","family":"Jurczyszyn","sequence":"additional","affiliation":[{"name":"Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, 31-066 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa","family":"Clay-Gilmour","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Epidemiology, Arnold School of Public Health, University of South Carolina, Greenville, SC 29208, USA"},{"name":"Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelika","family":"Stein","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A. T.","family":"Hildebrandt","sequence":"additional","affiliation":[{"name":"Department of Lymphoma\u2013Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Weinhold","sequence":"additional","affiliation":[{"name":"Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Buda","sequence":"additional","affiliation":[{"name":"Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa\/AOUP, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram\u00f3n","family":"Garc\u00eda-Sanz","sequence":"additional","affiliation":[{"name":"Diagnostic Laboratory Unit in Hematology, University 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Hematology, Experimental Hematology Unit, Vall d\u2019Hebron Institute of Oncology (VHIO), University Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daria","family":"Zawirska","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Hospital, 30-688 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzena","family":"W\u0105tek","sequence":"additional","affiliation":[{"name":"Holycross Medical Oncology Center, 25-735 Kielce, Poland"},{"name":"Institute of Hematology and Transfusion Medicine, 00-791 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan N.","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, 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Support Centre for Clinical Trials, 58-309 Walbrzych, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics, International Technology Park, Bangalore 560066, India"},{"name":"Manipal Academy of Higher Education (MAHE), Manipal 576104, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Mart\u00ednez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre, Complutense University, CNIO, CIBERONC, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7899-5966","authenticated-orcid":false,"given":"Sara","family":"Galimberti","sequence":"additional","affiliation":[{"name":"Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa\/AOUP, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Eugenia","family":"Sarasquete","sequence":"additional","affiliation":[{"name":"Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigaci\u00f3n del C\u00e1ncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5225-3921","authenticated-orcid":false,"given":"Edyta","family":"Subocz","sequence":"additional","affiliation":[{"name":"Department of Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elzbieta","family":"Iskierka-Ja\u017cd\u017cewska","sequence":"additional","affiliation":[{"name":"Department of Hematology, Medical University of Lodz, 90-419 Lodz, 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