Hypertensive Renal Injury

描述（由申请人提供）：在之前的资助期内，我们已经引入了一种新的方法来对近亲繁殖的啮齿动物品系进行遗传定位，该方法利用了在感兴趣的性状上不同的密切相关的品系。使用10K SNP图谱，我们已经表明，两个SHR系只有13%的基因组不同，但这些差异对高血压肾病的易感性有深远的影响。密切的遗传相似性使我们能够进行精细的定位，从而鉴定出影响血压和肾损伤的三个高度分辨的数量性状位点（QTL）。由于两系之间的相似性，这些QTL中的每一个都映射到一个小的，孤立的区域，其中两个SHR系来自不同的祖先。这些区域被广泛的同源遗传区（IBD）所包围，因此有助于将QTL的范围缩小到少数基因。在目前的研究中，我们建议确定每个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对血压和肾损伤都有影响。我们试图确定致病变异，并确定它是否首先作用于血压，然后对损伤产生继发性影响，或者它是否存在于产生损伤的途径中，然后导致肾功能降低和血压升高。另一种QTL对血压没有影响，似乎直接导致肾小球损伤。我们还确定了免疫球蛋白重链作为一个位点，在我们的系中包含广泛的变异。我们已经证明，这包括对IgG功能有重要影响的变异，包括无法将IgG从母亲转移到后代。这种变异与蛋白尿增加有关。我们建议研究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，以及母体-后代IgG转移是否参与风险传播。我们已经确定了人类中IgG的等位基因变异，这种变异广泛而古老，并且在功能上与我们在SHR系中检测到的变异同源。我们将进行大规模的人类群体遗传研究，以确定这种变异与人类肾功能的关系。

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.