Genetics of risk factor clustering in hypertension

自发性高血压大鼠(SHR)是研究最广泛的高血压遗传模型，与原发性高血压的人类一样，表现出许多代表心血管疾病危险因素的碳水化合物和脂代谢异常。然而，尽管进行了广泛的研究，高血压代谢危险因素聚集的基础仍然是一个谜。利用同基因和转基因菌株分离调节自发性高血压患者紊乱的脂肪酸和碳水化合物代谢的数量性状基因座(QTL)，是深入了解心血管危险因素聚集的遗传机制的有力策略。因此，本单位的主要目标是对参与心血管危险因素聚集的QTL进行分子鉴定 自发性高血压的疾病。我们已经确定了大鼠10号染色体的一个区域，该区域与自发性高血压大鼠的脂肪酸和胰岛素循环水平的调节有关。在这个染色体区域内，我们发现SHR在一个转录因子上存在独特的突变，该转录因子在肝脏控制葡萄糖和脂肪酸代谢方面至关重要。研究发现，将目标染色体区域从血压正常的棕色挪威品系转移到SHR背景中，可以降低循环中的脂肪酸和胰岛素水平。我们假设，导致肝脏转录因子过度表达的基因缺陷与最近发现的CD36中的SHR缺陷相互作用，从而促进无序脂肪 酸和碳水化合物的代谢。因此，我们将使用转基因和同源菌株相结合的方法，直接研究转录因子突变在自发性高血压病危险因素聚集发病机制中的作用。在这个模型中，如果这些突变不会导致脂肪或碳水化合物代谢紊乱，那么基于同源菌株减数分裂图谱的替代策略将被用于与自发性高血压病代谢紊乱相关的QTL的分子鉴定。尽管人与大鼠之间的比较必须谨慎，但可以预见的是，促进SHR心血管疾病危险因素聚集的QTL的分子识别最终将有助于阐明高血压患者碳水化合物和脂代谢紊乱的发病机制。

The spontaneously hypertensive rat (SHR) is the most widely studied genetic model of hypertension and like humans with essential hypertension, exhibits a number of abnormalities in carbohydrate and lipid metabolism that represent risk factors for cardiovascular disease. However, despite extensive research, the basis for the clustering of metabolic risk factors in hypertension remains a mystery. The use of Icongenic and transgenic strains to isolate quantitative trait loci (QTL) that mediate disordered fatty acid and carbohydrate metabolism in the SHR represents a powerful strategy for gaining insight into genetic mechanisms that underlie the clustering of cardiovascular risk factors. Accordingly, the primary objective of this unit is the molecular identification of QTL involved in the clustering of risk factors for cardiovascular disease in spontaneous hypertension. We have identified a region of rat chromosome 10 that is linked to the regulation of circulating levels of fatty acids and insulin in the SHR. Within this chromosome region, we have found that the SHR harbors unique mutations in a transcription factor critically important in the hepatic control of glucose and fatty acid metabolism. Transfer of the target chromosome region from the normotensive Brown Norway strain onto the SHR background has been found to decrease circulating levels of fatty acids and insulin. We hypothesize that a genetic defect causing hepatic overexpression of this transcription factor interacts with a recently identified SHR defect in Cd36 to promote disordered fatty acid and carbohydrate metabolism. Therefore, we will use a combination of transgenic and congenic strains to directly investigate the role of the transcription factor mutations in the pathogenesis of risk factor clustering in the SHR. In the event that these mutations do not contribute to disordered lipid or carbohydrate metabolism in this model, an alternative strategy based on meiotic mapping in congenic strains will be used for molecular identification of QTL linked to the metabolic disturbances in SHR. Although comparisons between humans and rats must be made with caution, it is anticipated that the molecular identification of QTL that promote the clustering of risk factors for cardiovascular disease in the SHR will ultimately shed light on the pathogenesis of disordered carbohydrate and lipid metabolism in patients with essential hypertension.