Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia

We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment...

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Autores: Benavente, Yolanda, Cabrera Serrano, Antonio José, Sánchez Maldonado, José Manuel, Rodríguez-Sevilla, Juan José, Reyes Zurita, Fernando J., Puiggros, Anna, García-Martín, Paloma, Espinet Solà, Blanca, González-Olmedo, Carmen, Moreno Aguado, Víctor, Carretero-Fernández, María, Pérez, Eva María, Li, Yi, Alcoceba, Miguel, Ibañez, M., Casabonne, Delphine, Berndt, Sonja I., Sainz, Juan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/228318
Acceso en línea:https://hdl.handle.net/2445/228318
Access Level:acceso abierto
Palabra clave:Leucèmia limfocítica crònica
Epidemiologia genètica
Chronic lymphocytic leukemia
Genetic epidemiology
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spelling Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemiaBenavente, YolandaCabrera Serrano, Antonio JoséSánchez Maldonado, José ManuelRodríguez-Sevilla, Juan JoséReyes Zurita, Fernando J.Puiggros, AnnaGarcía-Martín, PalomaEspinet Solà, BlancaGonzález-Olmedo, CarmenMoreno Aguado, VíctorCarretero-Fernández, MaríaPérez, Eva MaríaLi, YiAlcoceba, MiguelIbañez, M.Casabonne, DelphineBerndt, Sonja I.Sainz, JuanLeucèmia limfocítica crònicaEpidemiologia genèticaChronic lymphocytic leukemiaGenetic epidemiologyWe investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.American Society of Hematology2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/228318Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1182/bloodadvances.2025017345Blood Advances, 2025, vol. 9, num. 23, p. 6076-6089https://doi.org/10.1182/bloodadvances.2025017345cc by-nc-nd (c) Cabrera Serrano, Antonio José et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2283182026-05-27T06:46:51Z
dc.title.none.fl_str_mv Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
title Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
spellingShingle Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
Benavente, Yolanda
Leucèmia limfocítica crònica
Epidemiologia genètica
Chronic lymphocytic leukemia
Genetic epidemiology
title_short Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
title_full Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
title_fullStr Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
title_full_unstemmed Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
title_sort Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia
dc.creator.none.fl_str_mv Benavente, Yolanda
Cabrera Serrano, Antonio José
Sánchez Maldonado, José Manuel
Rodríguez-Sevilla, Juan José
Reyes Zurita, Fernando J.
Puiggros, Anna
García-Martín, Paloma
Espinet Solà, Blanca
González-Olmedo, Carmen
Moreno Aguado, Víctor
Carretero-Fernández, María
Pérez, Eva María
Li, Yi
Alcoceba, Miguel
Ibañez, M.
Casabonne, Delphine
Berndt, Sonja I.
Sainz, Juan
author Benavente, Yolanda
author_facet Benavente, Yolanda
Cabrera Serrano, Antonio José
Sánchez Maldonado, José Manuel
Rodríguez-Sevilla, Juan José
Reyes Zurita, Fernando J.
Puiggros, Anna
García-Martín, Paloma
Espinet Solà, Blanca
González-Olmedo, Carmen
Moreno Aguado, Víctor
Carretero-Fernández, María
Pérez, Eva María
Li, Yi
Alcoceba, Miguel
Ibañez, M.
Casabonne, Delphine
Berndt, Sonja I.
Sainz, Juan
author_role author
author2 Cabrera Serrano, Antonio José
Sánchez Maldonado, José Manuel
Rodríguez-Sevilla, Juan José
Reyes Zurita, Fernando J.
Puiggros, Anna
García-Martín, Paloma
Espinet Solà, Blanca
González-Olmedo, Carmen
Moreno Aguado, Víctor
Carretero-Fernández, María
Pérez, Eva María
Li, Yi
Alcoceba, Miguel
Ibañez, M.
Casabonne, Delphine
Berndt, Sonja I.
Sainz, Juan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia limfocítica crònica
Epidemiologia genètica
Chronic lymphocytic leukemia
Genetic epidemiology
topic Leucèmia limfocítica crònica
Epidemiologia genètica
Chronic lymphocytic leukemia
Genetic epidemiology
description We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/228318
url https://hdl.handle.net/2445/228318
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1182/bloodadvances.2025017345
Blood Advances, 2025, vol. 9, num. 23, p. 6076-6089
https://doi.org/10.1182/bloodadvances.2025017345
dc.rights.none.fl_str_mv cc by-nc-nd (c) Cabrera Serrano, Antonio José et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Cabrera Serrano, Antonio José et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society of Hematology
publisher.none.fl_str_mv American Society of Hematology
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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