New approaches to genetic predisposition for hemorrhagic stroke in sickle cell disease

Abstract

Hypertension has not traditionally been considered a significant problem in sickle cell disease (SCD) but that view is changing. 1 In the general population hypertension leads, among other things, to small vessel disease of the kidney and brain and to intracerebral hemorrhage, which are important complications of SCD. Although SCD is the most common monogenetic disease, its wide phenotypic variation has, for the most part, eluded satisfactory explanation. Except for coinheritance of alpha thalassemia and certain genes that affect fetal hemoglobin production, genomic studies have not converged on clear genetic risk markers for important complications such as stroke 2 although promising candidates have recently been proposed. 3 Specific genomic risk indicators for intracranial hemorrhage have not been reported. Although first ischemic stroke has been greatly reduced by regular red cell transfusion initiated on the basis of risk stratification by transcranial Doppler ultrasound 4 (STOP Protocol) there has been no corresponding reduction in intracranial hemorrhage inSCD. 5 With increased survival and decreased burden of ischemic stroke, intracerebral hemorrhage (ICH) will become an increasingly important problem. Robust predictors could lead to targeted prevention and reduction of this important type of stroke.Our understanding of risk for hemorrhagic stroke in SCD comes primarily from the Cooperative Study of Sickle Cell Disease. 6 This was an important effort to characterize the common phenotypes including stroke (ischemic and hemorrhage) but these data are over 30 years and the hemorrhagic stroke predictive model was based on only 27 events.Transcranial Doppler ultrasound is very effective in guiding transfusion or hydroxyurea to prevent ischemic stroke but does not clearly identify those at risk for hemorrhagic stroke. The existing phenotype-based risk model from the cooperative study is not specific enough to support clinical trials. There is a critical need to modernize our research strategies to find robust models if we are to reduce hemorrhagic stroke.We propose a shift in perspective. For example, in patients without SCD, several genes have been linked to intracerebral hemorrhage. 7 Ongoing efforts are developing stroke genomics from an African perspective 8,9 including achieving a better understanding of the genomics of predisposing factors such as hypertension. 10 The H3Africa Project was established by the US National Institutes of Health and the Wellcome Trust to develop capacity in genomic research in Africa, including specific projects focusing on assessment of perceptions about public health interventions to increase awareness, early detection and prevention of SCD-related complications 11 and the Sickle Pan-African Research Consortium (SPARCO) 12 that aims to develop infrastructure for sickle cell disease research, health care, education, and training in Africa. Instead of looking at thesepatients as individuals with SCD who typically happen to be black, we believe a better approach is to view them a...