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首页> 外文学位 >Evaluation of Genetic Variants Influencing Susceptibility to Type 2 Diabetes Associated End-Stage Kidney Disease and Associated Phenotypes in African and European Americans.
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Evaluation of Genetic Variants Influencing Susceptibility to Type 2 Diabetes Associated End-Stage Kidney Disease and Associated Phenotypes in African and European Americans.

机译：评估非洲人和欧洲人对2型糖尿病相关的终末期肾脏疾病和相关表型易感性的遗传变异。

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摘要

There is strong clinical and epidemiological evidence supporting a genetic link between type 2 diabetes associated end-stage kidney disease (T2D-ESKD) and African ancestry. Incidence and prevalence of T2D-ESKD, in addition to non-diabetic forms of ESKD, are markedly higher in African Americans compared to all other ethnicities even after adjustment for socioeconomic factors. Familial aggregation studies also support a strong genetic component to T2D-ESKD in African Americans. In this series of studies we examined this health care disparity from a genetics perspective by leveraging state-of-the-art genetic methodologies, including whole exome sequencing and bioinformatic tools, in an effort to further elucidate the genetic architecture of T2D-ESKD and non-T2D ESKD in several samples of African Americans, and to a lesser extent, in European Americans.;Data from these investigations provided wide-ranging genetic insights into T2D-ESKD, non-T2D ESKD, and also T2D in the absence of kidney disease. We have implicated rare- and low-frequency missense variants in the gene NPHS1 (which codes for the protein nephrin) that contribute to ESKD in the general African American population. Previously, NPHS1 variants were believed to contribute to monogenic diseases and uncommon forms of nephropathy. Moreover, we identified novel roles for the gene RREB1, coding for the ras responsive element binding protein 1, with implications for T2D, T2D-ESKD, and non-T2D ESKD in populations of both African and European ancestry. Data from an additional study demonstrate that genetic variations in the complement factor H gene (CFH) influence susceptibility to common, non-diabetic forms of ESKD in African Americans. Previously, CFH had been linked primarily to IgA nephropathy and dense deposit disease (DDD) in Asian and European populations.;Data from the aforementioned studies, in addition to those in the Appendix, provide new insights into T2D, T2D-ESKD, and non-T2D ESKD in both African and European Americans. The ultimate goals of any genetic study are to aid in prognostication of disease risk, provide biologic insights into disease pathogenesis, and to identify tractable drug targets. The investigations presented here expand our knowledge of the genetic underpinnings of T2D, T2D-ESKD, and non-T2D ESKD, laying the foundational framework for future studies aiming to construct a comprehensive genetic prognostication panel for T2D-ESKD and non-T2D ESKD, in addition to identifying a novel drug target (RREB1 ) which may have implications for T2D, T2D-ESKD, and non-T2D ESKD.
机译：有强有力的临床和流行病学证据支持2型糖尿病相关的终末期肾病（T2D-ESKD）与非洲血统之间存在遗传联系。与非其他形式的ESKD相比，非ESKD形式的T2D-ESKD的发病率和患病率，即使在调整了社会经济因素之后，与所有其他种族相比也明显高于其他种族。家族聚集研究还支持非洲裔美国人T2D-ESKD的强大遗传成分。在这一系列研究中，我们从遗传学的角度，通过利用最新的遗传学方法，包括整个外显子组测序和生物信息学工具，从遗传学的角度检查了这种卫生保健差距，以进一步阐明T2D-ESKD和非T2D-ESKD的遗传结构。 -T2D ESKD在数个非裔美国人样本中（在较小程度上在欧洲美国人中）；这些研究的数据为T2D-ESKD，非T2D ESKD以及没有肾脏疾病的T2D提供了广泛的遗传学见解。我们在基因NPHS1（编码蛋白nephrin）中牵涉到罕见和低频错义变异体，这些变异体在一般的非裔美国人人群中促成了ESKD。以前，人们认为NPHS1变体会导致单基因疾病和罕见的肾病。此外，我们确定了基因RREB1的新角色，该基因编码ras反应元件结合蛋白1，对非洲和欧洲血统的人群中的T2D，T2D-ESKD和非T2D ESKD具有影响。来自另一项研究的数据表明，补体因子H基因（CFH）的遗传变异会影响非洲裔美国人对常见的非糖尿病形式ESKD的易感性。以前，CFH主要与亚洲和欧洲人群中的IgA肾病和致密性沉积物疾病（DDD）相关联;上述研究的数据以及附录中的数据为T2D，T2D-ESKD和非T2D，T2D-ESKD提供了新的见解。 -T2D ESKD在非洲人和欧洲人中都使用。任何基因研究的最终目的都是帮助疾病风险的预后，提供对疾病发病机理的生物学见解，并确定易于治疗的药物靶标。本文介绍的研究拓宽了我们对T2D，T2D-ESKD和非T2D ESKD遗传基础的认识，为未来研究奠定了基础框架，旨在为T2D-ESKD和非T2D ESKD构建全面的基因预后专家组。除了确定可能对T2D，T2D-ESKD和非T2D ESKD有影响的新型药物靶标（RREB1）之外。

著录项

  • 作者

    Bonomo, Jason Andrew.;

  • 作者单位

    Wake Forest University.;

  • 授予单位 Wake Forest University.;
  • 学科 Genetics.;Pathology.;Epidemiology.;Medicine.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 184 p.
  • 总页数 184
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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