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

Hdl Handle:
http://hdl.handle.net/10675.2/36
Title:
Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen.
Authors:
Adams, Gaye T; Snieder, Harold; McKie, Virgil C; Clair, Betsy; Brambilla, Donald; Adams, Robert J; Kutlar, Ferdane; Kutlar, Abdullah
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 > or = 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 (TNFalpha), 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.
Citation:
BMC Med Genet. 2003 Jul 18; 4:6
Issue Date:
10-May-2004
URI:
http://hdl.handle.net/10675.2/36
DOI:
10.1186/1471-2350-4-6
PubMed ID:
12871600
PubMed Central ID:
PMC183831
Type:
Journal Article; Research Support, U.S. Gov't, P.H.S.
ISSN:
1471-2350
Appears in Collections:
Comprehensive Sickle Cell Center: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorAdams, Gaye Ten_US
dc.contributor.authorSnieder, Harolden_US
dc.contributor.authorMcKie, Virgil Cen_US
dc.contributor.authorClair, Betsyen_US
dc.contributor.authorBrambilla, Donalden_US
dc.contributor.authorAdams, Robert Jen_US
dc.contributor.authorKutlar, Ferdaneen_US
dc.contributor.authorKutlar, Abdullahen_US
dc.date.accessioned2010-09-24T21:15:44Z-
dc.date.available2010-09-24T21:15:44Z-
dc.date.issued2004-05-10en_US
dc.identifier.citationBMC Med Genet. 2003 Jul 18; 4:6en_US
dc.identifier.issn1471-2350en_US
dc.identifier.pmid12871600en_US
dc.identifier.doi10.1186/1471-2350-4-6en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/36-
dc.description.abstractBACKGROUND: 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 > or = 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 (TNFalpha), 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.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAdolescenten_US
dc.subject.meshAfrican Americans / geneticsen_US
dc.subject.meshAnemia, Sickle Cell / complicationsen_US
dc.subject.meshCase-Control Studiesen_US
dc.subject.meshCerebrovascular Disorders / complications / diagnosis / geneticsen_US
dc.subject.meshChilden_US
dc.subject.meshChild, Preschoolen_US
dc.subject.meshDNA / chemistry / geneticsen_US
dc.subject.meshGenetic Predisposition to Disease / geneticsen_US
dc.subject.meshGenetic Testing / methodsen_US
dc.subject.meshGenome, Humanen_US
dc.subject.meshHumansen_US
dc.subject.meshPhenotypeen_US
dc.subject.meshPolymorphism, Single Nucleotide / geneticsen_US
dc.subject.meshRandom Allocationen_US
dc.subject.meshRisk Factorsen_US
dc.subject.meshUltrasonography, Doppler, Transcranialen_US
dc.titleGenetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, U.S. Gov't, P.H.S.en_US
dc.identifier.pmcidPMC183831en_US
dc.contributor.corporatenameComprehensive Sickle Cell Centeren_US
dc.contributor.corporatenameGeorgia Institute for Prevention of Human Diseases and Accidentsen_US
dc.contributor.corporatenameDepartment of Pediatricsen_US
dc.contributor.corporatenameDepartment of Neurologyen_US

Related articles on PubMed

All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.