Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen.
Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen.
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镰状细胞疾病儿童脑血管疾病的遗传危险因素：病例对照协会研究和全基因组筛查的设计。
DOI：
10.1186/1471-2350-4-6
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发表时间：
2003-07-18
影响因子：
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通讯作者：
Kutlar, Abdullah
中科院分区：
文献类型：
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作者：
Adams, Gaye T;Snieder, Harold;McKie, Virgil C;Clair, Betsy;Brambilla, Donald;Adams, Robert J;Kutlar, Ferdane;Kutlar, Abdullah
镰状细胞病的表型异质性可能是多种遗传因素及其与镰状细胞突变相互作用的结果。高经颅多普勒（TCD）速度定义了镰状细胞病儿童的一个亚组，他们发展为缺血性卒中的风险增加。导致高TCD速度（即脑血管疾病）发展并最终导致中风的遗传因素尚未得到很好的表征。我们设计了一项病例-对照关联研究，以阐明遗传多态性作为镰状细胞病儿童高TCD速度测量的脑血管疾病危险因素的作用。该研究将包括两个部分：候选基因研究和全基因组筛选，将在230例病例和400例对照中进行。病例将包括在卒中预防试验中的镰状细胞性贫血（STOP）研究中随机分配的130例患者（TCD≥200 cm/s）以及在STOP II筛查中发现的其他100例高TCD患者。对照400例TCD速度正常（TCD < 170 cm/s）的镰状细胞病患者。候选基因研究将涉及20个候选基因的28个遗传多态性分析。多态性包括凝血因子基因（凝血因子V、凝血酶原、纤维蛋白原、因子VII、因子XIII、PAI-1）、血小板活化/功能（GpIIb/IIIa、GpIb IX-V、gpiia /IIa）、血管反应性（ACE）、内皮细胞功能（MTHFR、血栓调节素、VCAM-1、E-选择素、l -选择素、p -选择素、ICAM-1）、炎症（TNFα）、脂质代谢（Apo A1、Apo E）和细胞粘附（VCAM-1、E-选择素、l -选择素、p -选择素、ICAM-1）的突变。我们将对来自230例病例和400例对照的合并DNA样本进行全基因组范围的验证单核苷酸多态性（snp）筛选，以研究其他多态性与高危表型的可能关联。高通量SNP基因分型将通过MALDI-TOF技术使用Sequenom的MassARRAY™系统进行。通过阐明候选基因在高TCD发生中的作用，本研究将为镰状细胞病脑血管疾病表型的遗传危险因素提供重要信息。对大量snp的全基因组筛选可能揭示新的多态性与脑血管疾病和镰状细胞病卒中的关联。
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. 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. 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.