GENETICS OF DIABETIC NEPHROPATHY IN HISPANICS

西班牙裔糖尿病肾病的遗传学

• 批准号: 6660718
• 负责人: Susanne B Nicholas
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660718
• 关键词: ACE inhibitors; Hispanic Americans; albuminuria; clearance rate; clinical research; cooperative study; creatine; diabetes mellitus genetics; diabetic nephropathy; family genetics; genetic polymorphism; genetic susceptibility; genome; genotype; human genetic material tag; human subject; human therapy evaluation; kidney disorder chemotherapy; linkage mapping; noninsulin dependent diabetes mellitus; pathologic process; pharmacogenetics; phenotype; quantitative trait loci; racial /ethnic difference

Diabetic nephropathy is the leading cause of end-stge renal disease (ESRD) in the United States. In addition to significant morbidity, diabetic ESRD heralds increased mortality with more than 50% of patients dying within two years of starting dialysis. There is strong evidence that diabetic nephropathy is genetically determined as it aggregates in families. This proposal is submitted in response to RFA-DK-99-005. We propose to study the genetics of diabetic nephropathy in Hispanics with type 2 diabetes. This proposal will focus on Hispanics because they have a strong propensity for development of type 2 diabetes and diabetic nephropathy, making them ideal for genetic studies. This proposal comprises two components. In the first component, we will use both qualitative and quantitative genetic approaches. For qualitative analysis, both concordant relative-pair and discordant sibpair approaches will be used and families will be ascertained through a with diabetes and advanced diabetic renal disease. For quantitative analyses, albuminuria and creatine clearance will be utilized as quantitative traits and sibpairs will be ascertained through a proband with type 2 diabetes. For quantitative analysis, albuminuria and creatine clearance will be utilized as quantitative traits and sibpairs will be ascertained through a proband with type 2 diabetes. The second component is a pharmacogenetic study that aims at evaluating the relation between genetic polymorphisms and the response of nephropathy to angiotensin converting enzyme (ACE) inhibitors. Successful completion of this project will result in the identification of genes that confer susceptibility to diabetic nephropathy. Characterization of the products of these genes will enhance our understanding of the pathogenesis of diabetic renal disease and lead to development of new preventive and therapeutic strategies. Moreover, availability of genetic markers for diabetic nephropathy will allow early identification of patients at risk who should be targeted for intensive glycemic and blood pressure control. The pharmacogenetic component of this proposal will yield new information about the relation between genetic polymorphisms and the response to therapy with ACE inhibitors. Thus, patients who are not likely to respond can be identified early in the course of the disease and treated with alternative medications such as angiotensin II receptor blockers combined with strict glycemic control. Finally, studying Hispanics will provide information which we now lack regarding the pathogenesis and genetics of diabetic nephropathy in this rapidly growing segment of the population. Achieving the goals of this proposal will culminate in a marked reduction in the incidence of diabetic ESRD with a tremendous human and socioeconomic impact.

糖尿病肾病是终末期肾病（ESRD）在美国的主要原因。除了显著的发病率外，糖尿病ESRD还预示着死亡率的增加，超过50%的患者在开始透析后两年内死亡。有强有力的证据表明，糖尿病肾病是由遗传决定的，因为它在家族中聚集。该提案是根据RFA-DK-99-005提交的。我们建议研究西班牙裔2型糖尿病患者糖尿病肾病的遗传学。该提案将重点关注西班牙裔，因为他们有很强的2型糖尿病和糖尿病肾病的发展倾向，使他们成为基因研究的理想选择。这项建议包括两个部分。在第一个组成部分，我们将使用定性和定量遗传方法。在定性分析中，将采用一致性亲属对和非一致性兄弟对方法，并通过糖尿病和晚期糖尿病肾病患者确定家族。对于定量分析，蛋白尿和肌酸清除率将被用作定量特征，并通过先证2型糖尿病患者确定兄弟姐妹。对于定量分析，蛋白尿和肌酸清除率将被用作定量特征，并通过先证2型糖尿病患者确定兄弟姐妹。第二个组成部分是药理学研究，旨在评估遗传多态性与肾病对血管紧张素转换酶（ACE）抑制剂的反应之间的关系。这个项目的成功完成将导致对糖尿病肾病易感性基因的鉴定。这些基因产物的表征将增强我们对糖尿病肾病发病机制的理解，并导致新的预防和治疗策略的发展。此外，糖尿病肾病遗传标记的可用性将允许早期识别有风险的患者，他们应该针对强化血糖和血压控制。这一提议的药理学组成部分将产生关于遗传多态性与ACE抑制剂治疗反应之间关系的新信息。因此，不太可能有反应的患者可以在病程早期识别，并使用替代药物治疗，如血管紧张素II受体阻滞剂结合严格的血糖控制。最后，研究西班牙裔将提供我们现在缺乏的关于糖尿病肾病的发病机制和遗传学的信息，在这一快速增长的人群中。实现这一建议的目标将最终显著降低糖尿病ESRD的发病率，并产生巨大的人类和社会经济影响。