Genetic Mechanisms of Hypertension - from Mutation to Cellular Function

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Hypertension, or elevated blood pressure, affects more than one billion people worldwide. As a major risk factor for morbidity and mortality from diseases such as stroke, heart attacks, heart failure and kidney failure, it contributes to more than nine million deaths each year. Yet, many patients are not diagnosed or do not receive appropriate treatment. The overarching goal of this proposal is to expand our knowledge of the genetics and pathophysiology of hypertension, with a focus on the hormonal regulation of blood pressure by the so-called renin-angiotensin-aldosterone system. In the first project, we aim to identify new disease genes in families with primary hyperaldosteronism. Primary aldosteronism is the most common form of secondary hypertension and is typically caused by aldosterone-producing adrenal adenomas or bilateral adrenal hyperplasia. We have previously identified mutations in ion channel genes that cause aldosterone-producing adenomas and/or familial hyperaldosteronism (KCNJ5, CACNA1D, CACNA1H), but many families do not carry mutations in any of the known disease genes.In a second project, we aim to characterize the genomic landscape of reninomas, rare kidney tumors that produce renin and cause hypertension. We will identify tumor-specific (somatic) point mutations and larger deletions or duplications that may explain the increased renin production and proliferation in these tumors. The underlying mechanisms could have implications for patients with more common forms of renin excess, such as renal-artery stenosis. Lastly, we propose to study the interactions and regulation of the potassium channel KCNJ5, with the goal to define its role in human adrenal gland physiology.To achieve these goals, we will use cutting-edge genomic and proteomic technologies. For disease gene discovery, we will sequence all protein-coding genes (the exome) of patients with primary aldosteronism as well as reninomas and corresponding normal samples. We will implement an up-to-date next-generation sequencing analysis pipeline on the high-performance computing cluster in Düsseldorf. For the identification of interacting proteins, advanced mass spectrometry tools will be used.We believe that this approach, linking clinically important questions to molecular genetics and physiology, will result in the identification of new genes, proteins and pathways for hypertension diagnosis, drug discovery and personalized medicine.