INTERMEDIATE PHENOTYPE AND RISK OF DIABETIC NEPHROPATHY

描述：(根据申请者的摘要改编)强有力的证据表明，长期被认为具有肾病特定风险的1型糖尿病(DM)患者中，有30%-40%的患者具有这种风险，这是由于两个因素：血糖控制和基因。遗传因素似乎与高血压过程有关，因为它们与高血压家族史和红血球Na：Li逆向转运增加有关。一些涉及肾素-血管紧张素系统(RAS)的基因已经成为吸引人的详细研究的候选基因，包括涉及血管紧张素原基因ACE和AT1受体的多态性。对复杂的人类特征进行成功的遗传分析的一个主要障碍是它们的多因素决定，特别是病原学的异质性。因此，仅利用远缘表型作为二分性状的研究进展有限。提高病原学同质性的一个有效方法是采用中间表型，这是一种生理或生化特征，用于识别特定的患者亚群，以便与感兴趣的基因相关。中间表型也可以提供对负责的生理机制的洞察。本研究旨在确定上位关系中这些基因中的一个或多个的多态性是否与血管紧张素介导的肾脏循环控制的改变有关，该改变易导致糖尿病肾病，并阐明基因、血糖控制和这些生理异常的表达之间的相互作用。成功识别与特定基因多态相关的中间表型将有助于深入了解当前的治疗方法、识别有明确风险的患者的新方法以及改进的预防措施。

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.