Omics based strategies for precision medicine in hypertension and cardiovascular disease.

Studentship strategic priority area: Basic and Clinical Research
Keywords:Hypertension, Endocrinology, miRNAs, Precision Medicine, Bioinformatics.

High Blood pressure affects up to 50% of the general population and is the major risk factor for cardiovascular disease. Up to 15% of hypertension has an endocrine cause resulting from excessive hormone production and leading to a range of co-morbidities that include stroke, heart failure, atrial fibrillation, left ventricular hypertrophy and obesity. While endocrine hypertension is readily treatable, its accurate diagnosis is time-consuming and costly, which delays the administration of appropriate treatment.
Like other forms of hypertension, endocrine hypertension has a genetic component that predisposes individuals to disease. Recent studies identify microRNAs as important regulators of genetic processes. MicroRNAs are small (~22 nucleotide) non-coding RNAs that bind to specific target messenger RNAs, resulting in gene silencing through translation inhibition or mRNA degradation, thereby altering gene expression and protein levels. They have been shown to play a key role in numerous important cellular processes such as oncogenesis and cell proliferation, while our own previous studies also demonstrate a significant effect of microRNAs on hormone secretion, specifically the adrenal corticosteroids that play such a key role in certain forms of endocrine hypertension. Crucially, microRNAs are released by tissues into the bloodstream where they circulate in a stable, cell-free form, with the potential to serve as stable and accessible biomarkers for specific disease states. For this reason, circulating miRNAs represent not only a valuable diagnostic tool but may also be markers of processes that lead to disease and therefore potential therapeutic targets.
We hypothesise that circulating miRNA levels are altered in endocrine hypertension and that they can be used as a minimally invasive method to differentiate the various endocrine hypertension subtypes. We are currently part of a large international study (ENSAT-HT) and we have measured circulating miRNAs in a large cohort of carefully-phenotyped human subjects with endocrine hypertension. These extensive circulating miRNA profiles will now be studied in greater detail to investigate their diagnostic potential and their role in the underlying pathophysiological mechanisms of these conditions. This translational project will combine our extensive experience of cardiovascular endocrinology research with cutting-edge molecular, analytical and bioinformatic methods.
A better understanding of endocrine hypertension and its associated co-morbidities is central to developing new approaches for managing cardiovascular risk and outcome. Identifying a distinctive circulating miRNA signature that could be exploited for early and efficient diagnosis of affected patients would permit targeted management of patients, bringing significant health and economic benefits. Furthermore, this data could pinpoint novel regulatory mechanisms, thus identifying new types of therapy and better-targeted personalised treatments.