Genetic factors modifying sickle cell disease severity

Abstract

Sickle cell disease (SCD) is a monogenic disorder caused by a single base mutation but despite its apparent genetic simplicity, the clinical phenotype is hugely variable. In addition to environmental factors, family and epidemiological studies indicate that genetic variants co-inherited with the sickle mutation have a key role in modifying the disease course. This article provides an overview of the genetic modifi ers of SCD known to date. Co-inheritance of thalassemia and persistent fetal hemoglobin (HbF) production are established major genetic modifi ers but they do not explain the full spectrum of the phenotypic variability of SCD. While characterization of some of the key variants and pathways involved in HbF regulation have provided new therapeutic targets for HbF reactivation, generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifi ers yet to be discovered. Elucidation of new genetic modifi ers may also provide an insight into other “ldruggable” targets for therapeutic intervention.