15 research outputs found
Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen
BACKGROUND: The 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. METHODS: We 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. DISCUSSION: It 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
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Free protein S deficiency in acute ischemic stroke. A case-control study
Deficiency of free protein S, a naturally occurring anticoagulant, may be acquired in the setting of acute illness and increasingly has become recognized as a possible stroke risk factor. We sought to determine whether free protein S deficiency is associated with acute cerebral infarction among older individuals at risk for stroke.
Free protein S was measured by Laurell rocket immunoelectrophoresis in 94 adults admitted for acute cerebral infarction and in 94 hospitalized control subjects of similar age, sex, and race. Patients with a history of cerebrovascular disease, acute thrombotic or hematologic diseases, or medical conditions known to cause free protein S deficiency were excluded from the control group.
The percentage of patients with free protein S deficiency (< 20% normal total protein S) was similar in the case and control groups (21% versus 20%, respectively). Among all subjects, free protein S deficiency was more common in blacks than nonblacks (34% versus 13%, p = 0.001). A very low free protein S (< 15% normal total protein S) was more frequent among case patients than control subjects (11% versus 5%), but this trend failed to reach statistical significance.
Free protein S deficiency is common among hospitalized patients, even in the absence of a recognized predisposing condition. Our findings indicate that acquired deficiency of free protein S is not a major risk factor for ischemic stroke