Hypertensive Renal Injury

描述(由申请人提供)：在之前的资助期间，我们引入了一种新的方法来绘制近交系啮齿动物品系的基因图谱，该方法利用了在感兴趣的特征上不同的密切相关的品系。使用10K SNP图谱，我们发现两个SHR株系的基因组只有13%的差异，但这些差异对高血压肾病的易感性有深远的影响。紧密的遗传相似性使我们能够进行精细的定位，从而识别出三个影响血压和肾脏损伤的高分辨率数量性状基因座(QTL)。由于这些品系之间的相似性，这些QTL中的每一个都映射到一个小的、孤立的区块，在那里两个SHR品系来自不同的祖先。这些区块被广泛的降序完全相同(IBD)的区域包围，因此有助于狭义地定义QTL，直到少数基因。在目前的研究中，我们建议识别每个QTL中导致高血压肾病增加的基因，并了解它们的作用机制。一个QTL对血压和肾脏损伤都有影响。我们试图找出原因变异，并确定它是首先作用于血压，继而对损伤产生影响，还是存在于产生损伤的途径中，然后导致肾功能下降和血压升高。另一个QTL对血压没有影响，似乎直接导致肾小球损伤。我们还发现免疫球蛋白重链是一个在我们的品系中包含广泛变异的位点。我们已经证明，这包括对免疫球蛋白功能有重要影响的变异，包括不能将免疫球蛋白从母亲转移到后代。这种变异与蛋白尿的增加有关。我们建议调查由免疫球蛋白重链差异编码的免疫功能改变是否有助于易感SHR系肾脏疾病的出现，以及母子免疫球蛋白转移是否参与风险的传递。我们已经在人类的免疫球蛋白中发现了广泛而古老的等位基因变异，这种变异在功能上与我们检测到的跨SHR系的变异是同源的。我们将进行一项大规模的人类群体遗传学研究，以确定这种变异与人类肾功能的关联。

DESCRIPTION (provided by applicant): In the prior funding period we have introduced a new approach to genetic mapping in inbred rodent strains that exploits closely related lines differing in traits of interest. Using a 10K SNP map, we have shown that two SHR lines differ at only 13% of their genomes, but that these differences have a profound effect on susceptibility to hypertensive renal disease. The close genetic similarity has allowed us to perform fine mapping that has resulted in the identification of three highly resolved quantitative trait loci (QTL) affecting blood pressure and renal injury. Because of the similarity between the lines, each of these QTL maps to a small, isolated block where the two SHR lines have descended from different ancestors. These blocks are surrounded by extensive regions that are identical-by-descent (IBD) and thus help to narrowly define the QTL's, down to a small number of genes. In the present study we propose to identify the genes in each QTL that contribute to increased hypertensive renal disease and to understand the mechanisms by which they act. One QTL has effects on both blood pressure and renal injury. We seek to identify the causative variation and determine whether it acts first on blood pressure with secondary effects on injury or whether it lies in a pathway that produces injury that then leads to reduced renal function and increased blood pressure. Another QTL has no effect on blood pressure and appears to lead to glomerular damage directly. We have also identified the immunoglobulin heavy chain as a locus containing extensive variation across our lines. We have shown that this includes variation with important effects on IgG function including the inability to transfer IgG from mother to offspring. This variation associates with increased albuminuria. We propose to investigate whether alterations in immune function that are encoded by differences in the heavy chain of immunoglobulin contribute to the emergence of renal disease in the susceptible SHR line and whether maternal-offspring IgG transfer is involved in the transmission of risk. We have identified allelic variatio in IgG in humans that is widespread and ancient and that is functionally homologous to the variation we detected across SHR lines. We will perform a large-scale human population genetic study to determine the association of this variation with renal function in humans.