Abstract
BackgroundThe phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. High transcranial doppler (TCD) velocities define a subgroup of children with sickle cell disease who are at increased risk for developing ischemic stroke. The genetic factors leading to the development of a high TCD velocity (i.e. cerebrovascular disease) and ultimately to stroke are not well characterized.MethodsWe have designed a case-control association study to elucidate the role of genetic polymorphisms as risk factors for cerebrovascular disease as measured by a high TCD velocity in children with sickle cell disease. The study will consist of two parts: a candidate gene study and a genomewide screen and will be performed in 230 cases and 400 controls. Cases will include 130 patients (TCD ≥ 200 cm/s) randomized in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study as well as 100 other patients found to have high TCD in STOP II screening. Four hundred sickle cell disease patients with a normal TCD velocity (TCD < 170 cm/s) will be controls. The candidate gene study will involve the analysis of 28 genetic polymorphisms in 20 candidate genes. The polymorphisms include mutations in coagulation factor genes (Factor V, Prothrombin, Fibrinogen, Factor VII, Factor XIII, PAI-1), platelet activation/function (GpIIb/IIIa, GpIb IX-V, GpIa/IIa), vascular reactivity (ACE), endothelial cell function (MTHFR, thrombomodulin, VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1), inflammation (TNFα), lipid metabolism (Apo A1, Apo E), and cell adhesion (VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1). We will perform a genomewide screen of validated single nucleotide polymorphisms (SNPs) in pooled DNA samples from 230 cases and 400 controls to study the possible association of additional polymorphisms with the high-risk phenotype. High-throughput SNP genotyping will be performed through MALDI-TOF technology using Sequenom's MassARRAY™ system.DiscussionIt is expected that this study will yield important information on genetic risk factors for the cerebrovascular disease phenotype in sickle cell disease by clarifying the role of candidate genes in the development of high TCD. The genomewide screen for a large number of SNPs may uncover the association of novel polymorphisms with cerebrovascular disease and stroke in sickle cell disease.
Highlights
The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation
We propose to use a combination of a candidate gene association study and genomewide association scan in children with Hb SS at high (230 cases) or low (400 controls) risk for cerebrovascular disease as determined by their transcranial doppler (TCD) velocity
All 28 polymorphisms in 20 candidate genes that we propose to study have been shown to be associated with a hypercoagulable state or have been shown to be involved in pathways leading to the development of vasculopathy and, have a high probability to be related to the TCD velocity phenotype
Summary
The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. Sickle cell anemia (Hb SS) results from homozygosity for a A→T substitution at codon 6 of the β-globin gene (GAG→GTG) leading to a glutamic acid to valine (Glu→Val) substitution in the β globin chain of human adult hemoglobin. Despite this common genetic background, phenotypic expression of sickle cell disease is widely variable, ranging from a mild, asymptomatic course with survival into the sixth or seventh decade to a very severe course with multi-organ damage and early mortality [1]. Genetic factors that lead to the development of cerebrovascular disease and stroke in children with Hb SS are not well understood
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