INTERMEDIATE PHENOTYPE AND RISK OF DIABETIC NEPHROPATHY

糖尿病肾病的中间表型和风险

• 批准号: 7010656
• 负责人: NORMAN K HOLLENBERG
• 金额: $ 25.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010656
• 关键词: ACE inhibitors; angiotensin II; angiotensinogen; angiotensins; clinical research; diabetes mellitus genetics; diabetic nephropathy; disease /disorder classification; epidemiology; family genetics; gene environment interaction; gene expression; genetic polymorphism; genetic susceptibility; genotype; hemodynamics; human subject; hyperglycemia; insulin dependent diabetes mellitus; kidney circulation; peptidyl dipeptidase A; phenotype; renin angiotensin system

DESCRIPTION: (Adapted from the applicant's abstract) Strong evidence indicates that the long-recognized 30-40% of patients with type 1 diabetes mellitus (DM) who are at specific risk of nephropathy carry that risk because of two factors, glycemic control and genes. The genetic contributors appear to involve the hypertension process as they are associated with a strong family history of hypertension and increased red blood cell Na:Li countertransport. Several genes involving the renin-angiotensin system (RAS) have emerged as attractive candidates for detailed study, including polymorphism involving the angiotensinogen gene, ACE, and the AT1 receptor. A major barrier to successful genetic analysis of complex human traits is their multifactorial determination, specifically etiologic heterogeneity. Thus, the sole use of the distant phenotype as a dichotomous trait has limited progress. One powerful approach to increased etiologic homogeneity is to employ intermediate phenotypes, which are physiological or biochemical traits that identify specific subsets of patients for correlation with the gene of interest. The intermediate phenotype can also provide insight into the responsible physiological mechanisms. This study is designed to ascertain whether polymorphism in one or more of these genes in an epistatic relationship is associated with an alteration in angiotensin-mediated control of the renal circulation that predisposes to diabetic kidney disease, and to clarify the interaction between genes, glycemic control and expression of these physiologic abnormalities. Successful identification of intermediate phenotypes linked to specific genetic polymorphism would provide insight into current therapy, new approaches to identification of patients specifically at risk and improved preventative measures.

描述：（改编自申请人的摘要）强有力的证据表明，长期以来人们认为 30-40% 的 1 型糖尿病 (DM) 患者存在特定的肾病风险，这是由于血糖控制和基因这两个因素造成的。 。 遗传因素似乎与高血压过程有关，因为它们与强烈的高血压家族史和红细胞 Na:Li 反转运增加有关。 涉及肾素-血管紧张素系统 (RAS) 的几个基因已成为进行详细研究的有吸引力的候选基因，包括涉及血管紧张素原基因、ACE 和 AT1 受体的多态性。 成功对复杂人类特征进行遗传分析的一个主要障碍是其多因素决定，特别是病因异质性。 因此，单独使用远缘表型作为二分性状的进展有限。增加病因同质性的一种有效方法是采用中间表型，这是一种生理或生化特征，可识别特定的患者亚群与感兴趣的基因的相关性。 中间表型还可以深入了解负责的生理机制。 本研究旨在确定这些基因中一个或多个上位关系的多态性是否与血管紧张素介导的肾循环控制改变相关，从而诱发糖尿病肾病，并阐明基因、血糖控制之间的相互作用以及这些生理异常的表达。 成功鉴定与特定基因多态性相关的中间表型将为当前治疗提供深入了解，提供识别特定风险患者的新方法以及改进的预防措施。