Immunogenetics of Common Polygenic Renal Disease

我们试图继续从高血压相关肾脏疾病的大鼠模型的遗传研究中得出的一系列显著的见解。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遗传变异方面的进展表明，高血压肾损伤的最终中介是遗传决定的致病抗体的形成。虽然致病性抗体与罕见形式的肾脏疾病有关，但它们与人类高血压疾病没有关系，也没有被排除在此类疾病之外。在某种程度上，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重要影响。这个巨大的基因（人类的1.2Mb）在大鼠和人类中都具有非同寻常的结构多样性。因此，GWAS基因分型平台严重低估了IGH变异的代表性，并且不能充分考虑IGH中表型上重要的结构变异的存在。因此，我们使用的大鼠模型提供了一种工具来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，这是目前在人类群体遗传学中无法获得的。

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.