Written by Lauren Robertson, Science Writer
High blood pressure is the leading contributor to premature death worldwide. Detecting signs of hypertension – particularly secondary and curable hypertension such as primary aldosteronism (PA) – is critical to patient management and preventing cardiovascular complications.
In a new study, published in Nature, researchers have successfully identified genomic loci that appear to confer increased susceptibility to the development of PA.
At the heart of hypertension
PA is the most common form of secondary and curable hypertension. It is caused by an excessive amount of aldosterone being produced in the adrenal cortex thanks to an aldosterone producing adenoma (APA). A high level of this hormone in the body leads to increased sodium retention and potassium loss, causing elevated blood pressure.
Patients with PA are at an elevated risk of developing cardiovascular complications, such as stroke or heart failure, in comparison to those with essential or “primary” hypertension (high blood pressure that is not the result of a medical condition). There is also growing evidence that even in the general population, inappropriate aldosterone production may play a role in hypertension.
Despite this, PA is often missed in diagnosis, meaning patients do not receive treatment until many years after initial hypertension onset – at which point, potential cardiovascular complications are already established. Mutations in specific genes coding for ion channels and ATPases have been identified as causing PA, but the underlying causes of many cases remains unknown.
To get to the bottom of this, researchers performed GWAS on 562 cases of PA and 950 controls searching for single nucleotide polymorphisms. They identified 2 main loci on chromosomes 1 and 13, and an additional locus on chromosome 11. They also confirmed their findings in a meta-analysis of 1162 cases and 3296 controls.
Two candidate genes – CASZ1 on chromosome 1 and RXFP2 on chromosome 13 – were found to be expressed in different cell clusters in the adrenal gland, and their overexpression linked to mineralocorticoid biosynthesis. One explanation is that these genes could be linked to an increased susceptibility to developing PA through altering the mineralocorticoid output in the adrenal gland, and in turn influencing aldosterone production.
Interestingly, the locus on chromosome 13 was found to be specific to men and is stronger in bilateral adrenal hyperplasia (a form of PA) than APA. We know that men and women show differences in adrenal cortex physiology and adenoma development, and this could potentially have an impact on the different loci found across the two sexes. For example, circulating levels of the RXFP2 ligand are higher in males, and could explain the sex-dependent association of this gene with PA.
Alleviating arterial hypertension
Overall, this study highlights the first identified risk loci for primary aldosteronism and reveals new mechanisms involved in adrenal gland function and subsequent aldosterone excess. As the authors conclude: “The discovery that CASZ1 and RXFP2 are involved in the development of PA provides new pathophysiological insight and opens perspectives for the diagnosis and treatment of arterial hypertension.”