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

基本信息

  • 批准号:
    7430271
  • 负责人:
  • 金额:
    $ 84.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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) 是一种经典孟德尔疾病,由单一 β-血红蛋白基因突变引起。其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,我们表明单核苷酸多态性 (SNP) 与 HbSS 的选定亚表型(包括中风)以及“全局”严重性指数相关。我们还发现与其他人发现相关的基因存在关联新英格兰百岁老人研究 (CS) 指出,超长寿命 (EL) 很可能是一种复杂的遗传特征,可归因于相对缺乏易诱发的遗传和环境变异。与年龄相关的疾病,特别是心脏病、高血压和中风,此外,生存可能归因于可以防止衰老并延缓与年龄相关的疾病的发生的基因变异。我们的假设是,HbSS 患者和 CS 参与者的独立 GWA 将提供有关这两个独特且多样化人群表型易感性的广泛信息。此外,对这两组的分析进行比较,突出差异和相似之处,其次,与 2007 年公开的弗雷明汉心脏研究的 GWA 数据进行额外比较,将进一步增强和验证我们的研究结果。 GWA 和新颖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。具体来说,我们将: 对 -1800 名 HbSS 患者和 -1000 名无关的百岁老人进行 GWA;出于验证目的,使用 317K Illumina SNP 基因分型测定,对约 300 名无关的百岁老人后代、200 名后代队列对照和 125 名额外的 HbSS 患者进行了分析。通过当代关联分析和新颖的生物信息学,我们将比较与 HbSS 临床特征的关联,包括血压、生存、中风、骨坏死、阴茎异常勃起、腿部溃疡和疾病严重程度的综合测量,以及选定的实验室测量值,包括反映 HbSS 的乳酸脱氢酶和胎儿血红蛋白。 HbSS 的病理生理学要素。在 CS 受试者中,我们将检查遗传与临床特征的关联,包括身体和认知功能、功能状态以及与年龄相关的疾病(包括高血压、中风、心血管疾病和痴呆)的发病年龄。我们计划使用新颖的先进网络建模技术来描绘在中风和高血压等疾病中发挥关键作用的基因和通路。 (摘要完)

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Martin H. Steinberg其他文献

Accelerated healing of chronic sickle-cell leg ulcers treated with RGD peptide matrix. RGD Study Group.
RGD 肽基质治疗慢性镰状细胞性腿部溃疡的加速愈合。
  • DOI:
  • 发表时间:
    1994
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Doris L. Wethers;Gloria M. Ramirez;Mabel Koshy;Martin H. Steinberg;George Phillips;Robert;Siegel;James R. Eckrnan;Josef T. Prchal
  • 通讯作者:
    Josef T. Prchal
Biomarker Signatures of Sickle Cell Disease Severity
镰状细胞病严重程度的生物标志物特征
  • DOI:
    10.1182/blood.v130.suppl_1.690.690
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Mengtian Du;Sarah Van Ness;V. Gordeuk;M. Gladwin;P. Sebastiani;Martin H. Steinberg
  • 通讯作者:
    Martin H. Steinberg
Disorders of Hemoglobin: THE β THALASSEMIAS
血红蛋白疾病:β地中海贫血
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Martin H. Steinberg;B. G. Forget;D. R. Higgs;D. Weatherall
  • 通讯作者:
    D. Weatherall
Deferiprone versus Deferoxamine in Sickle Cell Disease: Results Deferiprone versus Deferoxamine in Sickle Cell Disease: Results from a 5-year long-term Italian multi-center randomized clinical from a 5-year long-term Italian multi-center randomized clinical trial. trial.
镰状细胞病中的去铁酮与去铁胺:结果 镰状细胞病中的去铁酮与去铁胺:一项为期 5 年的意大利长期多中心随机临床试验的结果。
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    G. Calvaruso;A. Vitrano;R. D. Maggio;Samir;Ballas;Martin H. Steinberg;P. Rigano;M. Sacco;Paul Telfer;D. Renda;Rita Barone;Aurelio Maggio
  • 通讯作者:
    Aurelio Maggio
Exagamglogene Autotemcel for Severe Sickle Cell Disease.
Exagamglogene Autotemcel 治疗严重镰状细胞病。
  • DOI:
    10.1056/nejmoa2309676
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    H. Frangoul;F. Locatelli;Akshay Sharma;Monica Bhatia;Markus Y. Mapara;Lyndsay Molinari;Donna A. Wall;Robert I Liem;Paul Telfer;Ami J Shah;Marina Cavazzana;S. Corbacioglu;D. Rondelli;Roland Meisel;Laurence Dedeken;S. Lobitz;M. de Montalembert;Martin H. Steinberg;Mark C Walters;Michael J. Eckrich;S. Imren;Laura Bower;C. Simard;Weiyu Zhou;Fengjuan Xuan;Phuong K Morrow;William E Hobbs;Stephan A Grupp
  • 通讯作者:
    Stephan A Grupp

Martin H. Steinberg的其他文献

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{{ truncateString('Martin H. Steinberg', 18)}}的其他基金

Sickle Cell Scholar
镰状细胞学者
  • 批准号:
    7828051
  • 财政年份:
    2009
  • 资助金额:
    $ 84.12万
  • 项目类别:
Genetic Diversity of Sickle Cell Anemia
镰状细胞性贫血的遗传多样性
  • 批准号:
    7848005
  • 财政年份:
    2009
  • 资助金额:
    $ 84.12万
  • 项目类别:
Genetic Diversity of Sickle Cell Anemia
镰状细胞性贫血的遗传多样性
  • 批准号:
    7939707
  • 财政年份:
    2009
  • 资助金额:
    $ 84.12万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7828053
  • 财政年份:
    2009
  • 资助金额:
    $ 84.12万
  • 项目类别:
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
  • 财政年份:
    2007
  • 资助金额:
    $ 84.12万
  • 项目类别:
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:
    7226507
  • 财政年份:
    2007
  • 资助金额:
    $ 84.12万
  • 项目类别:
Genetic Modulation of Sickle Cell Anemia
镰状细胞性贫血的基因调控
  • 批准号:
    7070296
  • 财政年份:
    2006
  • 资助金额:
    $ 84.12万
  • 项目类别:
Genetic Modulation of Sickle Cell Anemia
镰状细胞性贫血的基因调控
  • 批准号:
    7467398
  • 财政年份:
    2006
  • 资助金额:
    $ 84.12万
  • 项目类别:
Genetic Modulation of Sickle Cell Anemia
镰状细胞性贫血的基因调控
  • 批准号:
    7231659
  • 财政年份:
    2006
  • 资助金额:
    $ 84.12万
  • 项目类别:
CORE--Clinical Core
CORE--临床核心
  • 批准号:
    6900242
  • 财政年份:
    2004
  • 资助金额:
    $ 84.12万
  • 项目类别:

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肯塔基州临床和转化科学中心
  • 批准号:
    10185144
  • 财政年份:
    2016
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肯塔基州临床和转化科学中心
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  • 批准号:
    8048812
  • 财政年份:
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中枢神经系统在肝硬化相关加压素释放不当中的作用
  • 批准号:
    8601306
  • 财政年份:
    2009
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Role of the CNS in Inappropriate Vasopressin Release Associated with Cirrhosis
中枢神经系统在肝硬化相关加压素释放不当中的作用
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    8034764
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