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 (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.

Authors

Institutions

Publication Details

Journal
Blood Advances
Published
2025-09-03
DOI
https://doi.org/10.1182/bloodadvances.2025017345
Citations
1
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
1.63

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Juan Sáinz, Elena Cornejo-Calvo, Rossana Maffei, Federico Canzian et al.
1 citations
Blood Advances
Chronic Lymphocytic Leukemia Research
1.63
article

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

Juan Sáinz, Elena Cornejo-Calvo, Rossana Maffei, Federico Canzian, José Manuel Sánchez‐Maldonado, Sílvia de Sanjosé, Mario Luppi, Sílvia Ramos‐Campoy, Rosa Collado, Fernando J. Reyes‐Zurita, Aaron D. Norman, Eva María Pérez, Delphine Casabonne, Rob ter Horst, Antonio José Cabrera-Serrano, Tzu Hua Chen‐Liang, Mihai Gheorghe Netea, Juan José Rodríguez‐Sevilla, Joanna Kamaso, Stefano Landi, Miguel Alcoceba, Irene Gámez, Paloma García, Vı́ctor Moreno, Fatin Jannus, Blanca Espinet, Alyssa Clay‐Gilmour, Sonja I. Berndt, Mariam Ibáñez, Trinidad Dierssen‐Sotos, Susan L. Slager, Rafael Marcos‐Gragera, Daniele Campa, Nicola J. Camp, Anna Puiggros, Paula Ludovico, Roberto Marasca, Miguel Ángel López‐Nevot, Andrés Jerez, Carmen González‐Olmedo, Yang Li, Yolanda Benavente, María García‐Álvarez, Belém Sampaio‐Marques, James McKay, María Carretero-Fernández
article en
1 citations

Abstract

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.

Blood AdvancesVol. 9(23)
University of Pisa (IT), University of Modena and Reggio Emilia (IT), Hebron University (PS), Universidad de Cantabria (ES), Mayo Clinic (US), University of Bonn (DE), Austrian Academy of Sciences (AT), Radboud University Nijmegen (NL), University of South Carolina (US), Universidad de Granada (ES), German Cancer Research Center (DE), Universidad de Jaén (ES), University of Utah (US), Heidelberg University (DE), Catalan Institute for Water Research (ES), Huntsman Cancer Institute (US), Radboud University Medical Center (NL), Institut d'Investigació Biomédica de Bellvitge (ES), Josep Carreras Leukaemia Research Institute (ES), Hospital General Universitario Morales Meseguer (ES), Institut Català d'Oncologia (ES), Azienda Ospedaliero-Universitaria di Modena (IT), Radboud Institute for Molecular Life Sciences (NL), Instituto de Investigación Marqués de Valdecilla (ES), Institut Català de Traumatologia i Medicina de l'Esport (ES), Institut d'Investigació Biomèdica de Girona (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Universitario Virgen de las Nieves (ES), Complejo Hospitalario de Jaén (ES), National Cancer Institute (UA), CeMM Research Center for Molecular Medicine (AT), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), Hospital Casa de Salud (ES), Hospital Del Mar (ES), Instituto de Investigación Biomédica de Salamanca (ES), Municipal Institute for Medical Research (ES), Centro de Investigación del Cáncer (ES), National Cancer Institute (US), Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES), Duran i Reynals Hospital (ES), Mayo Clinic in Florida (US), Barcelona Institute for Global Health (ES), Parque Tecnológico de la Salud (ES), Centre for Individualised Infection Medicine (DE), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Fundació Clínic per a la Recerca Biomèdica (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Life & Brain (Germany) (DE), Centre international de recherche sur le cancer (FR), Vall d'Hebron Institute of Oncology (ES), Universitat de Barcelona (ES), University of Minho (PT)
University of Utah, Huntsman Cancer Foundation, Huntsman Cancer Institute, Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Instituto de Salud Carlos III, Institut de Recerca contra la Leucèmia Josep Carreras, National Cancer Institute
Openalex Percentile: Top 14%
Chronic Lymphocytic Leukemia Research
1.63
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.