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Review
. 2022 Dec;36(6):1097-1124.
doi: 10.1016/j.hoc.2022.06.006.

Genetic Modifiers of Sickle Cell Disease

Thomas Pincez  1 , Allison E Ashley-Koch  2 , Guillaume Lettre  3 , Marilyn J Telen  4
Affiliations
Review

Genetic Modifiers of Sickle Cell Disease

Thomas Pincez et al. Hematol Oncol Clin North Am. 2022 Dec.

Abstract

Sickle cell disease (SCD) is characterized by tremendous phenotypic heterogeneity across patients, but this clinical variability is poorly understood, thus motivating the search for genetic modifiers. The early identification of genetic variants that control fetal hemoglobin levels-a strong modifier of severity in SCD-served as a powerful example in support of these genetic experiments. Although there have been successful discoveries (eg, UGT1A, APOL1), many of the reported genetic associations remain controversial. The emergence of large-scale SCD cohorts and their integration into genetic and other omic-type research programs should bring SCD patients closer to the promises of precision medicine.

Keywords: Fetal hemoglobin; Genetic modifier; Genome-wide association study; Sickle cell disease.

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Conflict of interest statement

Disclosure G. Lettre. serves as an advisor to Unity Biotechnology, work unrelated to the present study. T. Pincez is a recipient of a Charles Bruneau Foundation fellowship award and merit scholarship program for foreign students from the Ministry of Education and Higher Education of Quebec. This work was funded by the Canadian Institutes of Health Research (PJT #156248) and the Canada Research Chair Program (GL), as well as the Doris Duke Charitable Foundation Charitable Foundation (grant #2021215, MJT) and grant DK124836 from the National Institute of Diabetes and Digestive and Kidney Diseases (AAK). A.E. Ashley-Koch have nothing to disclose. M.J. Telen. has research funding from Forma Therapeutics and CSL Behring, unrelated to the present study. M.J. Telen serves on advisory boards for Pfizer, Inc., and Novartis, for work unrelated to this study.

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