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: 7626008
• 负责人: Martin H. Steinberg
• 金额: $ 74.08万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626008
• 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; 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; 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; network models; novel; offspring; prognostic; programs; 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; 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; 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; network models; novel; offspring; 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）： 镰状细胞贫血（HBSS）是一种经典的门德尔氏病，是由单个β-血红蛋白基因突变引起的。它臭名昭著的表型变异性表明其他基因调节其许多亚表征。在基于候选基因的关联研究中，我们表明，单核苷酸多态性（SNP）与HBSS的选定亚表现型有关，包括中风，以及“全球”的严重性指数。我们还发现，与其他基因相关性，发现与寿命相关。归因于与年龄相关的疾病，尤其是心脏病，高血压和中风的遗传和环境变化，这可能归因于遗传性的差异，这些遗传变异是针对衰老的保护性的，这可能会延迟与年龄相关的疾病。 HBSS患者和CS参与者将提供有关这两个独特和多样化人群中表型倾向的广泛信息。此外，比较了这两组的分析，突出了差异和相似性，其次，与Framingham Heart研究中的GWA数据进行了其他比较，将于2007年公开使用，将进一步增强并验证我们的发现。 GWA和新型生物信息学方法将促进超越人口起源的表型/疾病风险模型的发展，因此代表了影响人类固有的疾病风险的关键遗传因素。具体而言，我们将：在-1800例HBSS患者和-1000名无关一百岁老人的患者中进行GWA；出于验证目的，使用317K Illumina SNP基因分型测定法，约有300个无关的百年代表后代，200个后代的同伴控制和125名HBSS患者。 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.在CS受试者中，我们将检查具有临床特征的遗传关联，包括身体和认知功能，功能状态和年龄在与年龄有关的状况发作时，包括高血压，中风，心血管疾病和痴呆症。我们计划使用新颖的高级网络建模技术来描述在中风和高血压等疾病中起着至关重要的作用的基因和途径。 （抽象的结尾）