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Updated: Jun 22, 2025
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Genetic Modifiers of Stroke in Patients with Sickle Cell Disease-A Scoping Review
Morohuntodun O Oni1, Miguel Brito2, Chloe Rotman3
1Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
Insights
Genetic factors influence stroke risk in sickle cell disease (SCD). Identifying these modifiers can lead to better stroke prevention strategies for SCD patients.
Area of Science:
- Genetics
- Neurology
- Hematology
Background:
- Sickle cell disease (SCD) presents with severe complications, notably a high prevalence of stroke (ischemic and hemorrhagic) and silent white matter changes.
- Understanding the underlying mechanisms and identifying individuals at higher risk for stroke is crucial for effective prevention and treatment in SCD patients.
Purpose of the Study:
- To review genetic modifiers associated with increased stroke risk in sickle cell disease.
- To highlight mechanisms such as Hemoglobin F (HbF) modulation, inflammation, cellular adhesion, endothelial disruption, and hemolysis.
Main Methods:
- Review of genetic studies, including genome-wide and exome-wide association studies (GWAS and EWAS).
- Analysis of identified key genetic modifiers linked to stroke risk in SCD.
Main Results:
- Several genetic modifiers have been associated with increased stroke risk in SCD through various biological pathways.
- Further research is needed to validate existing polymorphisms and discover new ones.
Conclusions:
- Genetic screenings could enable more targeted and effective stroke prevention in SCD.
- The findings will inform ongoing GWAS by the International Hemoglobinopathy Research Network (INHERENT) consortium.
Abstract:
Sickle cell disease (SCD) clinically manifests itself with a myriad of complications. Stroke, both ischemic and hemorrhagic, as well as silent white matter changes, occurs at a relatively high prevalence. Understanding why and in whom stroke is most likely to occur is critical to the effective prevention and treatment of individuals with SCD. Genetic studies, including genome- and exome-wide association studies (GWAS and EWAS), have found several key modifiers associated with increased stroke/stroke risk in SCD via mechanisms including Hemoglobin F (HbF) modulation, inflammation, cellular adhesion, endothelial disruption, and hemolysis. We present a review on the modifiers that have most clearly demonstrated an association to date. More studies are needed to validate other potential polymorphisms and identify new ones. Incorporating gene-focused screenings in clinical care could provide avenues for more targeted, more effective, and less toxic prevention of stroke in this population. The data from this review will be used to inform the initial GWAS performed by the International Hemoglobinopathy Research Network (INHERENT) consortium.
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