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https://hdl.handle.net/1822/85628
Título: | Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization |
Autor(es): | Clavero, Esther Sanchez-Maldonado, José Manuel Macauda, Angelica Ter Horst, Rob Marques, Maria Belém Sousa Sampaio Jurczyszyn, Artur Clay-Gilmour, Alyssa Stein, Angelika Hildebrandt, Michelle A. T. Weinhold, Niels Buda, Gabriele García-Sanz, Ramón Tomczak, Waldemar Vogel, Ulla Jerez, Andrés Zawirska, Daria Wątek, Marzena Hofmann, Jonathan N. Landi, Stefano Spinelli, John J. Butrym, Aleksandra Kumar, Abhishek Martínez-López, Joaquín Galimberti, Sara Sarasquete, María Eugenia Subocz, Edyta Iskierka-Jażdżewska, Elzbieta Giles, Graham G. Rybicka-Ramos, Malwina Kruszewski, Marcin Abildgaard, Niels Verdejo, Francisco García Sánchez Rovira, Pedro da Silva Filho, Miguel Inacio Kadar, Katalin Razny, Małgorzata Cozen, Wendy Pelosini, Matteo Jurado, Manuel Bhatti, Parveen Dudzinski, Marek Druzd-Sitek, Agnieszka Orciuolo, Enrico Li, Yang Norman, Aaron D. Zaucha, Jan Maciej Reis, R. M. Markiewicz, Miroslaw Rodríguez Sevilla, Juan José Andersen, Vibeke Jamroziak, Krzysztof Hemminki, Kari Berndt, Sonja I. Rajkumar, Vicent Mazur, Grzegorz Kumar, Shaji K. Ludovico, Paula Nagler, Arnon Chanock, Stephen J. Dumontet, Charles Machiela, Mitchell J. Varkonyi, Judit Camp, Nicola J. Ziv, Elad Vangsted, Annette Juul Brown, Elizabeth E. Campa, Daniele Vachon, Celine M. Netea, Mihai G. Canzian, Federico Försti, Asta Sainz, Juan |
Palavras-chave: | Multiple myeloma Autophagy Genetic variants Genetic susceptibility |
Data: | 9-Mai-2023 |
Editora: | Multidisciplinary Digital Publishing Institute |
Revista: | International Journal of Molecular Sciences |
Citação: | Clavero, E.; Sanchez-Maldonado, J.M.; Macauda, A.; Ter Horst, R.; Sampaio-Marques, B.; Jurczyszyn, A.; Clay-Gilmour, A.; Stein, A.; Hildebrandt, M.A.T.; Weinhold, N.; et al. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization. Int. J. Mol. Sci. 2023, 24, 8500. https://doi.org/10.3390/ijms24108500 |
Resumo(s): | 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 hemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP corre lated 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. |
Tipo: | Artigo |
Descrição: | Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data. |
URI: | https://hdl.handle.net/1822/85628 |
DOI: | 10.3390/ijms24108500 |
ISSN: | 1661-6596 |
e-ISSN: | 1422-0067 |
Versão da editora: | https://www.mdpi.com/1422-0067/24/10/8500 |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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ijms-24-08500.pdf | 3,5 MB | Adobe PDF | Ver/Abrir |
Este trabalho está licenciado sob uma Licença Creative Commons