Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Geffen Kleinstern,Dennis P Robinson,Sara J Achenbach,Janet E Olson,Connie Lesnick ,J Brice Weinberg,Richard R Furman,Neil E Kay,Sameer A Parikh,Celine M Vachon,Laura Z Rassenti,Esteban Braggio,Tait D Shanafelt,Danielle M Brander,Nicholas Boddicker ,James R Cerhan,Timothy G Call,Kari G Rabe,Aaron D Norman,Curtis A Hanson,Thomas J Kipps,Susan L Slager

doi:10.1038/s41375-021-01344-9

Abstract

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Highlights

Chronic lymphocytic leukemia (CLL) is a neoplasm of mature B-cells, with at least 5 × 109 B-cells/L in the peripheral blood [1]
Sex, and family history of CLL, little is known about factors associated with risk of Monoclonal B-cell lymphocytosis (MBL)
1234567890();,: we reported an association of these 41 SNPs and the CLL-PRS with MBL risk in a small cohort of 95 familial MBLs; the vast majority (93%) of these were low-count MBL (LC-MBL) [20]

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a neoplasm of mature B-cells, with at least 5 × 109 B-cells/L in the peripheral blood [1]. These CLL cells typically co-express CD5, CD19, CD20dim and CD23, and exhibit a decrease in expression of surface immunoglobulin, CD20, and CD79b as compared to normal B cells [2, 3]. MBL clones are present in ~5–12% in the general population [6,7,8] with the prevalence rising to 15–22% in unaffected first- degree relatives of CLL patients [4, 9, 10]. Sex, and family history of CLL, little is known about factors associated with risk of MBL

Methods

Results

Conclusion