Immunogenetics of Common Polygenic Renal Disease

我们试图继续我们在高血压相关性肾脏疾病大鼠模型中进行的遗传学研究中出现的一系列非凡的见解。该模型从自然遗传变异中获得疾病易感性。我们在发现和证明致病基因变异方面的进展表明，高血压肾损伤的最终中介是由致病抗体的遗传决定的形成。虽然致病抗体与更罕见的肾脏疾病有关，但它们并未与人类高血压疾病有关，也没有被排除在此类疾病之外。在一定程度上，这可能是因为我们的工作表明，编码免疫球蛋白(IgH)基因的遗传变异对疾病风险有很大影响。这个大基因(人类为1.2mb)在大鼠和人类中都含有非同寻常的结构多样性。因此，GWAS基因分型平台严重不能代表IGH变异，并且不能充分考虑在IGH中存在的表型重要的结构变异。因此，我们使用的大鼠模型提供了一种工具，用于研究免疫球蛋白遗传变异在高血压肾损伤发病机制中的作用，目前人类群体遗传学无法获得这种作用。 在这项研究中，我们将利用我们构建的近交系同源高血压大鼠来了解遗传变异是如何产生疾病的致病机制的。我们将首先找出引起致病抗体的抗原来源。我们已经找到了这些抗原的细菌来源的证据，并将调查肠道细菌易位。然后，我们将研究致病抗体的靶点，以便将高血压引起的肾功能变化与遗传易感性疾病的出现联系起来。我们相信，这些研究可以为探索和研究人类疾病发病的类似机制提供一条途径。

We seek to continue the remarkable series of insights that have emerged from our genetic studies in a rat model of hypertension-associated renal disease. This model acquires disease susceptibility from natural genetic variation. Our progress in uncovering and proving the causative genetic variation indicates that the final mediator of hypertensive renal injury is the genetically determined formation of pathogenic antibodies. While pathogenic antibodies have been implicated in rarer forms of kidney disease, they have not been implicated in human hypertensive disease, neither have they been excluded from such disease. In part, this may be because our work shows that genetic variation in the gene encoding immunoglobulin (IGH) makes a major contribution to disease risk. This large gene (1.2Mb in humans) contains extraordinary levels of structural diversity in both rats and humans. As a result, GWAS genotyping platforms drastically under-represent IGH variation and the presence of phenotypically important structural variation in IGH cannot be adequately considered. The rat model we use therefore, provides a tool to investigate the role of genetic variation in immunoglobulin in the pathogenesis of renal injury in hypertension that is not currently accessible in human population genetics. In the present study we will exploit inbred congenic hypertensive rat lines we have constructed to understand how genetic variation creates a pathogenic mechanism of disease. We will first seek out the source of antigens that elicit disease-causing antibodies. We have developed evidence of bacterial origin of these antigens and will investigate gut bacterial translocation. We will then investigate the target of pathogenic antibodies in order to link the alteration in renal function induced by elevated blood pressure with the emergence of disease in the presence of genetic susceptibility. We believe these studies can guide a pathway to explore and investigate analogous mechanisms of disease pathogenesis in humans.