Associations of Chronic Lymphocytic Leukemia (CLL) Susceptibility Variants Across the CLL Etiologic Continuum

Background: Low-count monoclonal B-cell lymphocytosis (LC-MBL) is a precursor to chronic lymphocytic leukemia (CLL). Forty-one inherited susceptibility variants for CLL have been reported, but whether these variants impact CLL, through the initiation of the clone (LC-MBL) or progression of LC-MBL to CLL, is not well characterized. Methods: We evaluated 41 previously reported CLL susceptibility variants and the CLL polygenic risk score (CLL-PRS, a weighted score of the 41 variants) among a study of 8322 individuals who screened negative for MBL based on eight-color flow cytometry, 1601 individuals who screened positive for LC-MBL, and 2606 CLL patients. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for LC-MBL compared with MBL-negative individuals and for CLL compared with LC-MBL (herein labeled progression). Models were adjusted for age, sex, and genetic principal components. Results: Of the 41 variants, 22 (54%) were associated with LC-MBL and 20 (49%) with progression (all p < 0.05). The ORs for eight variants differed between LC-MBL risk and progression (false discovery rate, FDR < 0.05), including two (rs6708784, 2q13; rs391855, 16q24.1) with associations in opposite directions. The CLL-PRS was associated with both LC-MBL (OR = 1.77, 95% CI: 1.66–1.88, p = 3.7 × 10−68) and progression (OR = 1.45, 95% CI: 1.35–1.56, p = 8.1 × 10−24). Conclusions: The effects of individual CLL-risk variants vary across the etiological continuum of disease with a subset associated with clonal initiation of LC-MBL and clonal progression to different degrees, or even in opposite directions. The CLL-PRS may help identify individuals at elevated risk for both LC-MBL and progression to CLL.