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Open Access 01-12-2003 | Study protocol

Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen

Authors: Gaye T Adams, Harold Snieder, Virgil C McKie, Betsy Clair, Donald Brambilla, Robert J Adams, Ferdane Kutlar, Abdullah Kutlar

Published in: BMC Medical Genetics | Issue 1/2003

Abstract

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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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/4/6/prepub

Title: Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen
Authors: Gaye T Adams
Harold Snieder
Virgil C McKie
Betsy Clair
Donald Brambilla
Robert J Adams
Ferdane Kutlar
Abdullah Kutlar
Publication date: 01-12-2003
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2003
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-4-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen

Abstract

Background

Methods

Discussion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

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