Researchers map the genetics behind a rare autoimmune disease

Disease and treatment 19. may 2021 3 min Professor Eystein Sverre Husebye Written by Kristian Sjøgren

Autoimmune Addison’s disease is so rare that identifying the genes that cause it has been difficult. Researchers have now done this, making diagnosis easier.

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Researchers have mapped the genetic mutation associated with the development of autoimmune Addison’s disease, which destroys the adrenal cortex.

The mapped genes explain 40% of the hereditary component of the disease, and the research results were only possible because the Nordic countries are exceptionally good at establishing and maintaining national registries of people with very rare diseases.

This discovery may be used to identify possible future treatments but also to diagnose the disease earlier.

“The clinical perspective is that we can now tackle the disease with more specific therapies – and identify individuals who have it sooner than we do today. If we can diagnose earlier, we may also be able to stop the process before the immune system destroys the last remnant of the adrenal cortex,” explains a leading researcher behind the new study, Eystein Sverre Husebye, Professor, Department of Clinical Science, University of Bergen, Norway.

The research results have been published in Nature Communications.

People with autoimmune Addison’s disease cannot produce vital hormones

Autoimmune Addison’s is a very serious disease in which the immune system gradually destroys the cells in the adrenal cortex, causing adrenocortical failure.

The adrenal cortex produces several vital hormones, including cortisol, which is necessary for the immune system to function and for metabolizing carbohydrate.

It also produces aldosterone, which regulates the body’s salt and fluid balance so that the body does not excrete too much sodium in urine.

Destroying the adrenal cortex harms these functions. Nevertheless, many of the symptoms of autoimmune Addison’s disease are diffuse, such as muscle weakness, fatigue, nausea, vomiting, eating disorders, dizziness and diarrhoea. Hyperpigmentation of the skin and the mucous membrane is a specific sign. Left untreated, the disease can be fatal.

Fortunately, people with the disease can be treated, and doctors can prescribe tablets with the hormones the adrenal cortex no longer produces.

Often accompanied by other autoimmune diseases

An estimated 400–500 people have this disease in Denmark and about 1,000 in Norway, where Eystein Sverre Husebye carried out his research.

“Autoimmune Addison’s disease is a classic endocrine disorder that can be fatal. The incidence is about 5–6 per million people, which means 20–25 new cases per year in Norway. Because it is so rare, we have not had a very good overview of the genetic factors that influence its development,” says Eystein Sverre Husebye.

He explains that autoimmune Addison’s disease is very interesting for research because it is often accompanied by other autoimmune diseases.

About 10% also have type 1 diabetes, 5–6% have coeliac disease (gluten-sensitive enteropathy) and 10% of the women with autoimmune Addison’s disease have early menopause – already in their twenties.

“This is one reason to treat people as early as possible, so that women can remain fertile,” explains Eystein Sverre Husebye.

Analysed data from 1,600 individuals with Addison’s

Eystein Sverre Husebye and Olle Kämpe at Karolinska Institutet in Stockholm investigated the genetics behind autoimmune Addison’s disease by collecting data on 1,600 people from comprehensive national registries in Norway and Sweden.

The participants were tested for autoantibodies to the adrenal cortex to confirm that they had autoimmune Addison’s disease. The researchers then analysed their genomes by using blood samples and compared them with genomes from healthy people, identifying genetic variants especially associated with the development of the disease.

Genetic variants are small genetic differences between individuals that are associated with an increased risk of certain diseases.

Genetic variant makes the thymus leak

The researchers discovered several genes comprising 40% of the hereditary component for the development of autoimmune Addison’s disease.

They confirmed previous findings that had identified autoimmune Addison’s disease with variation in the human leukocyte antigen on chromosome 6p21 and implicated other well-established genes associated with susceptibility to autoimmune diseases such as PTPN22, CTLA4, CLEC16A. The study further identified BACH2 and AIRE as risk loci in autoimmune Addison’s disease.

According to Eystein Sverre Husebye, identifying AIRE is especially important.

“AIRE is known because one type of autoimmune Addison’s disease, polyendocrine syndrome type I, has mutations in AIRE. In this type, the thymus plays an important role by maturing the cells of the immune system. However, if AIRE does not function, autoimmune cells escape from the spleen and can attack the body’s own cells, including the adrenal cortex. We have shown that genetic variants in AIRE also play a role in the most common type of autoimmune Addison’s disease,” explains Eystein Sverre Husebye.

Genetics enables earlier diagnosis

Eystein Sverre Husebye explains that the new research results are promising because they provide greater insight into what goes wrong in the body when people develop autoimmune Addison’s disease.

This advances research by improving understanding of the immune system and how genetic defects can disrupt the balance so that it attacks the body’s own tissue.

However, the research results also have clinical applications.

Doctors can analyse the genetic variants associated with autoimmune Addison’s disease and thus more easily identify people with the disease, perhaps even before the first signs occur. This may become a clinical routine in the future.

“This could lead to earlier treatment, so that people can receive immunosuppressants well before the adrenal cortex is destroyed,” says Eystein Sverre Husebye.

Eystein Sverre Husebye also thinks that the discovery may be used to develop drugs that specifically target the genetic variants that cause autoimmune Addison’s disease to develop.

GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility" has been published in Nature Communications. In 2014, the Novo Nordisk Foundation awarded a grant to Eystein Husebye for the project The Mosaic of Autoimmunity Revealed by the Kaleidoscope of Autoimmune Polyendocrine Syndromes.

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