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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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Hauptverfasser: Clavero, Esther (VerfasserIn) , Sanchez-Maldonado, José Manuel (VerfasserIn) , Macauda, Angelica (VerfasserIn) , Ter Horst, Rob (VerfasserIn) , Sampaio-Marques, Belém (VerfasserIn) , Jurczyszyn, Artur (VerfasserIn) , Clay-Gilmour, Alyssa (VerfasserIn) , Stein, Angelika (VerfasserIn) , Hildebrandt, Michelle A. T. (VerfasserIn) , Weinhold, Niels (VerfasserIn) , Buda, Gabriele (VerfasserIn) , García-Sanz, Ramón (VerfasserIn) , Tomczak, Waldemar (VerfasserIn) , Vogel, Ulla (VerfasserIn) , Jerez, Andrés (VerfasserIn) , Zawirska, Daria (VerfasserIn) , Wątek, Marzena (VerfasserIn) , Hofmann, Jonathan N. (VerfasserIn) , Landi, Stefano (VerfasserIn) , Spinelli, John J. (VerfasserIn) , Butrym, Aleksandra (VerfasserIn) , Kumar, Abhishek (VerfasserIn) , Martínez-López, Joaquín (VerfasserIn) , Galimberti, Sara (VerfasserIn) , Sarasquete, María Eugenia (VerfasserIn) , Subocz, Edyta (VerfasserIn) , Iskierka-Jażdżewska, Elzbieta (VerfasserIn) , Giles, Graham G. (VerfasserIn) , Rybicka-Ramos, Malwina (VerfasserIn) , Kruszewski, Marcin (VerfasserIn) , Abildgaard, Niels (VerfasserIn) , Verdejo, Francisco García (VerfasserIn) , Sánchez Rovira, Pedro (VerfasserIn) , da Silva Filho, Miguel Inacio (VerfasserIn) , Kadar, Katalin (VerfasserIn) , Razny, Małgorzata (VerfasserIn) , Cozen, Wendy (VerfasserIn) , Pelosini, Matteo (VerfasserIn) , Jurado, Manuel (VerfasserIn) , Bhatti, Parveen (VerfasserIn) , Dudzinski, Marek (VerfasserIn) , Druzd-Sitek, Agnieszka (VerfasserIn) , Orciuolo, Enrico (VerfasserIn) , Li, Yang (VerfasserIn) , Norman, Aaron D. (VerfasserIn) , Zaucha, Jan Maciej (VerfasserIn) , Reis, Rui Manuel (VerfasserIn) , Markiewicz, Miroslaw (VerfasserIn) , Rodríguez Sevilla, Juan José (VerfasserIn) , Andersen, Vibeke (VerfasserIn) , Jamroziak, Krzysztof (VerfasserIn) , Hemminki, Kari (VerfasserIn) , Berndt, Sonja I. (VerfasserIn) , Rajkumar, Vicent (VerfasserIn) , Mazur, Grzegorz (VerfasserIn) , Kumar, Shaji K. (VerfasserIn) , Ludovico, Paula (VerfasserIn) , Nagler, Arnon (VerfasserIn) , Chanock, Stephen J. (VerfasserIn) , Dumontet, Charles (VerfasserIn) , Machiela, Mitchell J. (VerfasserIn) , Varkonyi, Judit (VerfasserIn) , Camp, Nicola J. (VerfasserIn) , Ziv, Elad (VerfasserIn) , Vangsted, Annette Juul (VerfasserIn) , Brown, Elizabeth E. (VerfasserIn) , Campa, Daniele (VerfasserIn) , Vachon, Celine M. (VerfasserIn) , Netea, Mihai G. (VerfasserIn) , Canzian, Federico (VerfasserIn) , Försti, Asta (VerfasserIn) , Sainz, Juan (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2023
In: International journal of molecular sciences
Year: 2023, Jahrgang: 24, Heft: 10, Pages: 1-20
ISSN:1422-0067
DOI:10.3390/ijms24108500
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.3390/ijms24108500
Verlag, kostenfrei, Volltext: https://www.mdpi.com/1422-0067/24/10/8500
Volltext
Verfasserangaben: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 and Juan Sainz

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245 1 0 |a Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma  |b a meta-analysis of three large cohorts and functional characterization  |c 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 and Juan Sainz 
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520 |a 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. 
650 4 |a autophagy 
650 4 |a genetic susceptibility 
650 4 |a genetic variants 
650 4 |a multiple myeloma 
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700 1 |a Macauda, Angelica  |e VerfasserIn  |4 aut 
700 1 |a Ter Horst, Rob  |e VerfasserIn  |4 aut 
700 1 |a Sampaio-Marques, Belém  |e VerfasserIn  |4 aut 
700 1 |a Jurczyszyn, Artur  |e VerfasserIn  |4 aut 
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700 1 |a Stein, Angelika  |e VerfasserIn  |4 aut 
700 1 |a Hildebrandt, Michelle A. T.  |e VerfasserIn  |4 aut 
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700 1 |a García-Sanz, Ramón  |e VerfasserIn  |4 aut 
700 1 |a Tomczak, Waldemar  |e VerfasserIn  |4 aut 
700 1 |a Vogel, Ulla  |e VerfasserIn  |4 aut 
700 1 |a Jerez, Andrés  |e VerfasserIn  |4 aut 
700 1 |a Zawirska, Daria  |e VerfasserIn  |4 aut 
700 1 |a Wątek, Marzena  |e VerfasserIn  |4 aut 
700 1 |a Hofmann, Jonathan N.  |e VerfasserIn  |4 aut 
700 1 |a Landi, Stefano  |e VerfasserIn  |4 aut 
700 1 |a Spinelli, John J.  |e VerfasserIn  |4 aut 
700 1 |a Butrym, Aleksandra  |e VerfasserIn  |4 aut 
700 1 |a Kumar, Abhishek  |e VerfasserIn  |4 aut 
700 1 |a Martínez-López, Joaquín  |e VerfasserIn  |4 aut 
700 1 |a Galimberti, Sara  |e VerfasserIn  |4 aut 
700 1 |a Sarasquete, María Eugenia  |e VerfasserIn  |4 aut 
700 1 |a Subocz, Edyta  |e VerfasserIn  |4 aut 
700 1 |a Iskierka-Jażdżewska, Elzbieta  |e VerfasserIn  |4 aut 
700 1 |a Giles, Graham G.  |e VerfasserIn  |4 aut 
700 1 |a Rybicka-Ramos, Malwina  |e VerfasserIn  |4 aut 
700 1 |a Kruszewski, Marcin  |e VerfasserIn  |4 aut 
700 1 |a Abildgaard, Niels  |e VerfasserIn  |4 aut 
700 1 |a Verdejo, Francisco García  |e VerfasserIn  |4 aut 
700 1 |a Sánchez Rovira, Pedro  |e VerfasserIn  |4 aut 
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SRT |a CLAVEROESTPOLYMORPHI2023 

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