- 2025-11-26
- Blood advances 9(23)
- Antonio José Cabrera-Serrano
- José Manuel Sánchez-Maldonado
- Juan José Rodríguez-Sevilla
- Fernando Jesús Reyes-Zurita
- Rosa Collado
- Anna Puiggros
- Elena Cornejo-Calvo
- Paloma García-Martín
- Rob Ter Horst
- Yolanda Benavente
- Andrés Jerez
- Stefano Landi
- Blanca Espinet
- Rossana Maffei
- Miguel Ángel López-Nevot
- Silvia Ramos-Campoy
- Carmen González-Olmedo
- Tzu-Hua Chen-Liang
- Víctor Moreno
- Fatin Jannus
- Rafael Marcos-Gragera
- María Carretero-Fernández
- Belém Sampaio-Marques
- Irene Gámez
- María García-Álvarez
- Nicola J Camp
- Trinidad Dierssen-Sotos
- Joanna Kamaso
- Eva María Pérez
- Aaron D Norman
- Mario Luppi
- Yang Li
- Miguel Alcoceba
- Daniele Campa
- Silvia de San José
- Roberto Marasca
- Paula Ludovico
- Alyssa Clay-Gilmour
- Federico Canzian
- Marian Ibañez
- Mihai G Netea
- James McKay
- Delphine Casabonne
- Sonja I Berndt
- Susan L Slager
- Juan Sainz
Study Design
- Type
- Meta-Analysis
- Population
- 5472 CLL cases and 726,465 controls across 4 independent populations
- Methods
- Meta-analysis of 4 populations examining 55,583 autophagy-related SNPs
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.