Genome-Wide Association Studies in Sickle Cell Anemia and in Centenarians

镰状细胞性贫血和百岁老人的全基因组关联研究

• 批准号: 7430271
• 负责人: Martin H. Steinberg
• 金额: $ 84.12万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-25 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430271
• 关键词: Abbreviations; Academic Medical Centers; Affect; Age; Aging; Bioinformatics; Biological Assay; Blood Pressure; Bone necrosis; Boston; Candidate Disease Gene; Cardiovascular Diseases; Centenarian; Clinical; Complex Genetic Trait; Condition; Data; Dementia; Development; Disease; Dissection; Elements; Equilibrium; Fetal Hemoglobin; Framingham Heart Study; Gene Mutation; Genes; Genetic; Genetic Variation; Genotype; Globin; Glomerular Filtration Rate; Hemoglobin; Hypertension; Inherited; Laboratories; Leg Ulcer; Linkage Disequilibrium; Longevity; Measurement; Measures; Methods; Modeling; Multicenter Studies; Nature; New England; Nitric Oxide; Oxidoreductase; Participant; Pathway interactions; Patients; Phenotype; Planning Techniques; Play; Population; Population Heterogeneity; Population Study; Predisposition; Premature Mortality; Priapism; Pulmonary Hypertension; Purpose; Relative (related person); Research; Research Personnel; Risk; Role; Severities; Severity of illness; Sickle Cell Anemia; Sickle Hemoglobin; Single Nucleotide Polymorphism; Stroke; Study Subject; Techniques; Transcend; Validation; Variant; abstracting; age related; base; cognitive function; cohort; computer based statistical methods; cooperative study; disorder risk; functional status; genetic association; genome wide association study; hydroxyurea; hypertensive heart disease; indexing; mecarzole; network models; novel; prognostic; programs

DESCRIPTION (provided by applicant): Sickle cell anemia (HbSS), a classical Mendelian disease is caused by a single beta-hemoglobin gene mutation. Its notorious phenotypic variability suggests that other genes modulate its many subphenotypes. In candidate gene-based association studies, we showed that single nucleotide polymorphisms (SNPs) were associated with selected subphenotypes of HbSS, including stroke, and with a 'global" severity index. We also found an association with genes others have found to be related to longevity. Exceptional longevity, (EL) has been noted by the New England Centenarian Study (CS) to very likely be a complex genetic trait that can be attributed to a relative lack of genetic and environmental variations that predispose to age-related diseases, particularly heart disease, hypertension and stroke. In addition, survival may be attributed to genetic variations that are protective against aging and that may delay the onset of age-related diseases. In this proposal, we focus on genome-wide association studies (GWA) in these 2 unique populations. Our hypothesis is that independent GWA in HbSS patients and the CS participants will provide extensive information about predisposition to phenotypes in these two unique and diverse populations. Moreover, a comparison of the analyses of these two groups, highlighting differences and similarities, and secondarily, additional comparisons with GWA data from the Framingham Heart Study to be publicly available in 2007 will further enhance and validate our findings. GWA and novel bioinformatic approaches will facilitate development of a model of phenotype/disease risk that transcends population origin and thus, represents key genetic factors affecting disease risk that are inherent to mankind. Specifically we will: perform GWA in -1800 patients with HbSS and -1000 unrelated centenarians; and for validation purposes, ~ 300 unrelated centenarian offspring, 200 offspring cohort controls and 125 additional HbSS patients, using the 317K Illumina SNP genotyping assay. With contemporary association analysis and novel bioinformatics we will compare associations with clinical features of HbSS including blood pressure, survival, stroke, osteonecrosis, priapism, leg ulcers and an integrated measure of disease severity and also selected laboratory measurements including lactic dehydrogenase and fetal hemoglobin that reflect pathophysiological elements of HbSS. In CS subjects, we will examine genetic associations with clinical features including physical and cognitive function, functional status and age at onset of age-related conditions including hypertension, stroke, cardiovascular disease and dementia. Using novel advanced network modeling techniques we plan to delineate genes and pathways that play crucial roles in diseases like stroke and hypertension. (End of Abstract)

描述（由申请人提供）： 镰状细胞性贫血（HbSS）是一种典型的孟德尔遗传病，由单个β-血红蛋白基因突变引起。它臭名昭著的表型变异表明，其他基因调节其许多亚表型。在基于候选基因的关联研究中，我们发现单核苷酸多态性（SNPs）与选定的HbSS亚表型（包括卒中）和“总体”严重程度指数相关。我们还发现了与其他人发现的与长寿有关的基因的关联。新英格兰百岁老人研究（CS）指出，异常长寿（EL）很可能是一种复杂的遗传性状，可归因于相对缺乏易患与年龄有关的疾病（特别是心脏病、高血压和中风）的遗传和环境变异。此外，存活率可能归因于基因变异，这些变异可以防止衰老，并可能延迟与年龄有关的疾病的发作。在这项提案中，我们专注于这两个独特人群的全基因组关联研究（GWA）。我们的假设是，HbSS患者和CS参与者的独立GWA将提供关于这两个独特且多样化的人群中表型易感性的广泛信息。此外，这两个群体的分析比较，突出的差异和相似之处，其次，与GWA数据的额外比较，从心脏研究的心脏Fractionary将在2007年公开，将进一步加强和验证我们的研究结果。GWA和新的生物信息学方法将促进超越人群起源的表型/疾病风险模型的开发，从而代表影响人类固有疾病风险的关键遗传因素。具体而言，我们将：在约1800名HbSS患者和约1000名无关的百岁老人中进行GWA;并且为了验证目的，使用317 K Illumina SNP基因分型测定，约300名无关的百岁老人后代、200名后代队列对照和125名另外的HbSS患者。通过现代关联分析和新的生物信息学，我们将比较HbSS与临床特征的关联，包括血压、生存率、卒中、骨坏死、阴茎异常勃起、腿部溃疡和疾病严重程度的综合指标，以及反映HbSS病理生理学要素的选定实验室指标，包括乳酸脱氢酶和胎儿血红蛋白。在CS受试者中，我们将研究遗传与临床特征的相关性，包括身体和认知功能，功能状态和年龄相关疾病（包括高血压，中风，心血管疾病和痴呆）的发病年龄。利用先进的网络建模技术，我们计划描绘在中风和高血压等疾病中起关键作用的基因和途径。(End摘要）