Identification of four autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia Open Access

• CDKN2A and BCL2 SNPs are newly linked to CLL risk, with CDKN2A rs3731204 showing the strongest association (p = 1.57×10⁻¹²).

• These variants are linked to altered gene expression (e.g., CDKN2A, ACTA2) and affect immune responses but not survival or treatment timing.

We investigated the influence of 55,583 autophagy-related single nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across four independent populations comprising 5,472 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 four populations identified, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, 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 mRNA expression levels in 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 IFNg, TRAIL, CD40, CCL20, and IL2RB proteins (p≤0.005). 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 four novel associations for CLL and provided insights into the biological pathways that influence CLL development.