GENETICS OF NEPHROPATHY IN HUMAN TYPE 2 DIABETES

只有不到30%的糖尿病患者会患上不可逆转的肾病。 对于肾病患者的糖尿病亲属来说，风险是3.5%到 比一般人口高出10倍。因此，遗传易感性 似乎区分了那些注定要患糖尿病的患者 肾病。我们建议使用一种新的方法来定位糖尿病易感基因 协和和非参数同胞对分析相结合的方法 不协调同胞、等位基因关联和数量性状分析 在有多个糖尿病兄弟姐妹的家庭中。将在以下位置测试链接 150对兄弟姐妹符合糖尿病，75对不符合糖尿病。 将首先测试已知基因的连锁和关联 建议的影响2型糖尿病、高血压、 其他人群或动物模型的肾病及其对血糖的影响 包括醛糖还原酶。将进行10 cM的基因组扫描以 绘制新基因图谱。将对潜在的肾病基因进行检测 与200例无血缘关系的肾病患者的相关性，并在 另外100对协调的和50对不协调的兄弟姐妹。其他内容 研究将绘制控制白蛋白的数量性状基因座 用方差分量方法研究糖尿病患者的排泄量 联动。最后，转化的淋巴细胞来自糖尿病患者和非糖尿病患者 家族性糖尿病家系成员将在正常血糖水平下进行研究 和高血糖条件下寻找临床前标志物 肾病。这些研究将在以下家庭中进行： 糖尿病易感性的基因组研究正在进行中。山梨醇 积累和醛糖还原酶的表达将被检查和测试 与醛糖还原酶基因连锁。钠氢交换 将被测量和测试与氢化钠的相关性 交换机1报文。将进行基因组扫描以绘制出 控制钠氢交换的数量性状基因座 确定该基因座是否会导致肾病。这些研究将 识别易感基因和含有易感基因的染色体区域 导致肾病，并将导致更好的理解 糖尿病肾病的治疗。

Fewer than 30 percent of diabetic patients get irreversible nephropathy. For diabetic relatives of patients with nephropathy the risk is 3.5 to 10-fold higher than the general population. Thus, genetic susceptibility appears to distinguish those diabetic patients destined to develop nephropathy. We propose to map diabetes susceptibility genes using an approach that combines nonparametric sib pair analysis of concordant and discordant sibs, allelic association, and quantitative trait analysis in families with multiple diabetic siblings. Linkage will be tested in 150 sib pairs concordant for diabetes and 75 discordant for diabetes. Linkage and association will first be tested for known genes and proposed loci that influence risk of Type 2 diabetes, hypertension, nephropathy in other populations or animal models, and glycemic effects including aldose reductase. A 10 cM genome scan will be conducted to map novel genes. Potential nephropathy loci will be tested for association in 200 unrelated patients with nephropathy, and tested in an additional 100 concordant and 50 discordant sib pairs. Additional studies will map the quantitative trait locus controlling albumin excretion in diabetic patients using a variance component approach to linkage. Finally, transformed lymphocytes from diabetic and nondiabetic members of familial diabetes pedigrees will be studied under euglycemic and hyperglycemic conditions to search for preclinical markers of nephropathy. These studies will be conducted in families for which a genome search for diabetes susceptibility is in progress. Sorbitol accumulation and aldose reductase expression will be examined and tested for linkage to the aldose reductase locus. Sodium hydrogen exchange will be measured and tested for correlation with sodium hydrogen exchanger 1 message. A genome scan will be undertaken to map the quantitative trait locus controlling sodium hydrogen exchange, and to determine whether this locus leads to nephropathy. These studies will identify genes and chromosomal regions containing genes that predispose to nephropathy, and will lead to an improved understanding better management of diabetic nephropathy.