A Scoping Review of Genetic Modifiers in Sickle Cell Disease: Pathways Driving Leg Ulcer Development and Progression

Abstract

The main objective of this scoping review is to evaluate the availability, methodologies, quality, and research gaps in literature on genetic modifiers of leg ulcers in sickle cell disease (SCD). SCD leg ulcers (SLUs) are a major complication in SCD, with their multifactorial evolution and limited treatment guidelines posing significant challenges. While genetic susceptibilities may eventually inform counseling and prognostication, current evidence remains exploratory and requires further validation.The study collates and assesses available research on genetic markers of sickle cell leg ulcers (SLUs) across all age groups, genders, races, and regions. A comprehensive search of PubMed and other major databases, including Google Scholar, Web of science, and Scopus, from 1998 to 2024, was performed. Findings highlight the need to complement clinical approaches with genetic insights to identify biomarkers critical for developing superior therapeutic interventions. Single nucleotide polymorphic markers (SNPs) associated with the Mitogen-Activated Protein Kinase (MAPK) and Small Mothers Against Decapentaplegic (SMAD) signaling pathways emerged as the most common genetic factors influencing SLU development. Significantly, the review emphasizes the need for Africa, where the burden of SCD is highest, to expand research ownership through collaboration and investments in randomized control trials. While the research terrain reflects economic disparities, strengthening local capacity could drive advancements in SLU management. In conclusion, integrating genetic knowledge into the management of SLUs is vital for improved outcomes, and addressing current research gaps is essential for guiding future evidence synthesis and interventions.