This week, we explore genomics’ role in primary aldosteronism – a hormone disorder that leads to high blood pressure
High blood pressure (or hypertension) is a common condition, affecting around 30% of adults. It is normally caused by a combination of genetic and environmental factors and is linked to an increased risk of many health problems, including heart attacks, strokes, kidney disease and vascular dementia.
For between 5% and 10% of people with hypertension, the cause is the overproduction of a hormone called aldosterone, which is part of the system that regulates the amounts of salt and water in the body.
Aldosterone is produced by the adrenal glands and stimulates the kidneys to increase the amount of salt reabsorbed into the bloodstream. Water in the blood rises to compensate, leading to increased blood volume and higher blood pressure. This type of hypertension is called primary aldosteronism.
Primary aldosteronism is usually caused by enlargement of the adrenal glands, or by noncancerous tumours called adenomas (sometimes referred to as ‘nodules’) in the adrenal glands that produce high levels of aldosterone.
The condition is resistant to treatment with standard hypertension therapies, so it is important that it is identified. Once diagnosed, it is treatable with specific aldosterone-antagonist medicines and can be cured in cases where adenomas can be removed by keyhole surgery.
Finding a genomic cause
Researchers have used genome-wide association studies (GWAS) to discover a number of genes that influence the formation of these aldosterone-producing adenomas. Most notably, they identified a variant in the KCNJ5 gene that is found in around 40% of people with these nodules. This variant affects the channels that control the flow of potassium in and out of the cells.
Interestingly, it appears that the KCNJ5 variant is most likely to be found in younger female patients that present with large adenomas; older men with smaller adenomas seem to be less likely to carry the variant.
Sudden onset during pregnancy
Some women without any previous history of hypertension can experience the sudden onset of primary aldosteronism during early pregnancy. If this is not identified, monitored and treated, it can lead to complications, the most common of which is pre-eclampsia.
A new study, published in Nature Genetics, has identified two gene variants responsible for this phenomenon.
Both variants are in genes that code for parts of the same molecular switch, known as a G protein. When both variants are present at the same time, the switch can be activated by human gonadotropic hormone (HCG) – a hormone produced during early pregnancy (and the type detected by pregnancy tests). This then causes the production of high levels of aldosterone and leads to primary aldosteronism.
Both variants must be present for HCG to activate the switch; if only one of the variants is present, the switch does not react to the hormone and the person will not develop the condition in this way.
Professor Morris Brown, who supervised the study at Queen Mary University of London and St Bart’s Hospital, said: “What was particularly satisfying is that recognition of the cause of hypertension in these women enabled them to complete a successful pregnancy, and that afterwards they were completely cured of hypertension by a procedure to remove the adrenal nodule, and were able to stop all their drugs.”