Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

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,...

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Main Authors: Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A. T. Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N. Hofmann, Stefano Landi, John J. Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G. Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D. Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I. Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K. Kumar, Paula Ludovico, Arnon Nagler, Stephen J. Chanock, Charles Dumontet, Mitchell J. Machiela, Judit Varkonyi, Nicola J. Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E. Brown, Daniele Campa, Celine M. Vachon, Mihai G. Netea, Federico Canzian, Asta Försti, Juan Sainz
Format: Article
Language:English
Published: MDPI AG 2023-05-01
Series:International Journal of Molecular Sciences
Subjects:
multiple myeloma
autophagy
genetic variants
genetic susceptibility
Online Access:https://www.mdpi.com/1422-0067/24/10/8500
Description
Summary: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; <i>p</i> < 1 × 10<sup>−9</sup>) 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, <i>CD46</i>, <i>IKBKE</i>, <i>PARK2</i>, <i>ULK4</i>, <i>ATG5</i>, and <i>CDKN2A</i> associated with MM risk (<i>p</i> = 4.47 × 10<sup>−4</sup>−5.79 × 10<sup>−14</sup>). Mechanistically, we found that the <i>ULK4</i><sub>rs6599175</sub> SNP correlated with circulating concentrations of vitamin D3 (<i>p</i> = 4.0 × 10<sup>−4</sup>), whereas the <i>IKBKE</i><sub>rs17433804</sub> SNP correlated with the number of transitional CD24<sup>+</sup>CD38<sup>+</sup> B cells (<i>p</i> = 4.8 × 10<sup>−4</sup>) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (<i>p</i> = 3.6 × 10<sup>−4</sup>). We also found that the <i>CD46</i><sub>rs1142469</sub> SNP correlated with numbers of CD19<sup>+</sup> B cells, CD19<sup>+</sup>CD3<sup>−</sup> B cells, CD5<sup>+</sup>IgD<sup>−</sup> cells, IgM<sup>−</sup> cells, IgD<sup>−</sup>IgM<sup>−</sup> cells, and CD4<sup>−</sup>CD8<sup>−</sup> PBMCs (<i>p</i> = 4.9 × 10<sup>−4</sup>−8.6 × 10<sup>−4</sup>) and circulating concentrations of interleukin (IL)-20 (<i>p</i> = 0.00082). Finally, we observed that the <i>CDKN2A</i><sub>rs2811710</sub> SNP correlated with levels of CD4<sup>+</sup>EMCD45RO<sup>+</sup>CD27<sup>−</sup> cells (<i>p</i> = 9.3 × 10<sup>−4</sup>). 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<sup>−</sup>, MCP-2<sup>−</sup>, and IL20-dependent pathways.
ISSN:1661-6596
1422-0067

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