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oai:repisalud.isciii.es:20.500.12105/231192024-11-28T16:59:47Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16959col_20.500.12105_16960
Repisalud author Clavero, Esther author Sanchez-Maldonado, José Manuel author Macauda, Angelica author Ter Horst, Rob author Sampaio-Marques, Belém author Jurczyszyn, Artur author Clay-Gilmour, Alyssa author Stein, Angelika author Hildebrandt, Michelle A T author Weinhold, Niels author Buda, Gabriele author García-Sanz, Ramón author Tomczak, Waldemar author Vogel, Ulla author Jerez, Andrés author Zawirska, Daria author Wątek, Marzena author Hofmann, Jonathan N author Landi, Stefano author Spinelli, John J author Butrym, Aleksandra author Kumar, Abhishek author Martinez-Lopez, Joaquin author Galimberti, Sara author Sarasquete, María Eugenia author Subocz, Edyta author Iskierka-Jażdżewska, Elzbieta author Giles, Graham G author Rybicka-Ramos, Malwina author Kruszewski, Marcin author Abildgaard, Niels author Verdejo, Francisco García author Sánchez Rovira, Pedro author da Silva Filho, Miguel Inacio author Kadar, Katalin author Razny, Małgorzata author Cozen, Wendy author Pelosini, Matteo author Jurado, Manuel author Bhatti, Parveen author Dudzinski, Marek author Druzd-Sitek, Agnieszka author Orciuolo, Enrico author Li, Yang author Norman, Aaron D author Zaucha, Jan Maciej author Reis, Rui Manuel author Markiewicz, Miroslaw author Rodríguez Sevilla, Juan José author Andersen, Vibeke author Jamroziak, Krzysztof author Hemminki, Kari author Berndt, Sonja I author Rajkumar, Vicent author Mazur, Grzegorz author Kumar, Shaji K author Ludovico, Paula author Nagler, Arnon author Chanock, Stephen J author Dumontet, Charles author Machiela, Mitchell J author Varkonyi, Judit author Camp, Nicola J author Ziv, Elad author Vangsted, Annette Juul author Brown, Elizabeth E author Campa, Daniele author Vachon, Celine M author Netea, Mihai G author Canzian, Federico author Försti, Asta author Sainz, Juan funder Unión Europea. Comisión Europea. Horizonte Europa funder Instituto de Salud Carlos III funder Marie Curie funder CRIS contra el Cáncer funder NIH - National Cancer Institute (NCI) (Estados Unidos) funder Federal Ministry of Education & Research (BMBF) funder Cancer Network of Excellence funder Fundacao para a Ciencia e a Tecnologia (FCT) 2024-09-16T08:17:12Z 2024-09-16T08:17:12Z 2023-05-09 Int J Mol Sci . 2023 ;24(10):8500 https://hdl.handle.net/20.500.12105/23119 37239846 10.3390/ijms24108500 1422-0067 International journal of molecular sciences 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. eng Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization research article