INTERMEDIATE PHENOTYPE AND RISK OF DIABETIC NEPHROPATHY

糖尿病肾病的中间表型和风险

• 批准号: 6565007
• 负责人: NORMAN K HOLLENBERG
• 金额: $ 23.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565007
• 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）有力证据表明，长期认可的30-40％的1型糖尿病患者（DM）患有肾病的特定风险，因为肾病的风险有两个因素，血糖控制和基因有两个因素。 遗传贡献者似乎涉及高血压过程，因为它们与高血压的强大家族病史和红细胞NA：LI逆转录的增加有关。 几种涉及肾素 - 血管紧张素系统（RAS）的基因已成为详细研究的有吸引力的候选者，包括涉及血管紧张素基因，ACE和AT1受体的多态性。 对复杂人类特征的成功遗传分析的主要障碍是它们的多因素确定，特别是病因异质性。 因此，将遥远的表型用作二分性状的唯一使用的进度有限。提高病因同质性的一种有力的方法是采用中间表型，这些表型是生理或生化特征，这些特征鉴定出患者的特定亚群以与感兴趣的基因相关。 中间表型还可以提供对负责任的生理机制的见解。 这项研究旨在确定上卑鄙关系中一个或多个这些基因中的多态性是否与血管紧张素介导的对肾脏循环的控制的改变有关，使肾脏循环对糖尿病肾脏疾病易患肾脏循环，并阐明基因之间的相互作用，Glaccemic对照。和这些生理异常的表达。 成功鉴定与特定遗传多态性相关的中间表型将为当前疗法提供洞察力，这是针对有风险的患者的新方法，并改善了预防措施。