"Mythbusters” identified the gene that may cause a rare autoimmune disorder

A group of researchers leveraged their location to tackle questions about the rare autoimmune disorder, Addison’s disease.

May 7, 2021
Natalya Ortolano, PhD
"Mythbusters” identified the gene that may cause a rare autoimmune disorder

Immune cells have an inconvenient tendency to go rogue sometimes, recognizing their host’s cells as intruders and attacking them. In Addison’s disease, the immune system targets the adrenal gland, which produces hormones important in stress responses, such as cortisol and adrenaline. People need these hormones to survive, so patients with Addison’s disease depend on hormone pills.

Eystein Sverre Husebye, a professor in the department of clinical medicine at the University of Bergen, and his team conduct experiments at the bench and in the clinic to find better treatments for this devastating disease.

Since Addison’s disease is so rare, finding enough patients to conduct any kind of study is next to impossible. What makes the difference for Husebye’s team? Location. Addison’s disease is far more prevalent in Norway: 200 in every million people in Nordic countries have the disease, which is twenty times the rate in the United States.

In the past year, Husebye’s team identified the first genetic risk variants for this hereditary disease. They also showed that some Addison’s disease patients have residual adrenal function long after initial diagnosis, contrary to the common belief that patients lost all function as disease progressed.

“We like to think of ourselves as ‘mythbusters’ because there's been just a common thought that once you get Addison's disease, it's over and out. Sooner or later, you will lose all ability to produce corticosteroids,” said Ase Bjorvatn Saevik, a researcher in Husebye’s laboratory.

Ase Bjorvatn Saevik of department of clinical sciences at the University of Bergen in the lab. Photographer: Fredrik Bjorvatn Sævik.

Saevik landed in Husebye’s lab by chance. In her second year of medical school, she stumbled on a book he authored about Addison’s disease in the library and “fell in love.” She contacted Husebye and he offered her a PhD project. She accepted enthusiastically and got to work after she finished medical school.

Saevik wants to understand why the severity of disease varies so much between patients. Some patients are completely debilitated — so fatigued they can’t even work — while others can manage their disease easily.

To explore this mystery, she and her team tested the corticosteroid levels in nearly 200 patients and found that 30% still produced adrenal hormones; they expected to find only 10%. The researchers are recruiting more patients to increase their sample size and strengthen their data, and they plan to follow these patients for years or even decades to understand how the disease progresses. 

However, the underlying genetic differences between patients who retain some adrenal function and those who don’t aren’t clear. Small sample size makes it difficult to use strategies like genome wide association studies (GWAS) to explore how different variants amongst patients contribute to these differential effects.

“[We could] see if there are...genetic differences between those who do have residual function and those who don't. But currently, that would probably be quite difficult, because... the genome is so huge. And in order to get statistically significant results from this, you need quite large cohorts, which has been one of the problems for Addison's disease,” said Ellen Christine Røyrvik, a geneticist in Husebye’s lab.

Røyrvik can’t explain genetic differences between Addison’s disease patients with different symptoms, but she can tell you what genetic variant may have caused the disease to begin with.

Røyrvik co-authored an article published in Nature Communications in February that detailed the first GWAS in patients with Addison’s disease. She and her team identified two new genetic risk variants in the coding region of an immune-related protein not found in other autoimmune disorders. 

Experts think that this is an exciting find. “It’s a very solid paper,” said Gregory Gibson, the director of the center for integrative genomics at Georgia Institute of Technology, who was not involved in this study. “A skeptic could argue that they haven’t done enough to prove that the [variants] are [in] the true causal gene, but in this case, the balance of evidence is pretty extreme.”

Husebye’s group collaborated with researchers from the Karolinska Institutet in Sweden. The researchers used samples from two large biobanks to identify 1223 Addison’s disease patients and 4097 healthy individuals. Analysis of these samples revealed associated mutations commonly found in other autoimmune disorders. For example, they identified a variant of HLA, a cell surface protein that alerts immune effector cells to an infection. However, two genetic variants in a gene called AIRE may be specific to Addison’s disease.

“Perhaps the most important finding in this study is that we associate a gene, the AIRE gene, that has not been linked to other autoimmune diseases. It is, we believe, specifically linked to this disease, and that gives new insight into the background of the biology of this particular disease,” said Daniel Eriksson from the department of medicine, Karolinska Institutet and co-first author of the paper.

AIRE mutations are present in another autoimmune disorder known as APS-1, which is essentially a monogenic form of Addison’s disease. However, the authors uncovered new mutations that are distinct from those in APS-1. The genetic connection between APS-1 and Addison’s disease makes sense, but things aren’t always so straightforward in research.

Ellen Christine Røyrvik, a geneticist in Husebye’s lab, who co-authored the GWAS study identifying two genetic variants unique to Addison’s disease. Provided by Røyrvik.

“It was a bit surprising, and also very pleasing, how clean [the data] looked, and how, on the whole, everything was so easy to explain,” said Røyrvik. “Everything fit together in quite a nicely cell focused package.”

One expert, however, thinks the genetic variants identified in AIRE deserve a closer look. One variant occurs in only 2% of healthy individuals, indicating that this mutation has deleterious effects. However, the other mutation appears in 90% of healthy individuals. It’s likely that a combination of other genetic and environmental risk factors contribute to Addison’s disease.

“We tend to teach that diseases are bad, mutations are bad, and therefore mutations cause disease. This data is really showing it’s not as simple as that,” said Gibson. “A lot of these associations from GWAS are variants that are causing disease, but potentially they are having some other benefit.”

Gibson proposed that evolutionary analysis could determine if this variant was selected for during natural selection and help identify the true disease causing mutations.

Overall, AIRE may be the key to understanding how Addison’s disease develops and how to effectively treat it. Before they can develop any drugs, the Nordic researchers are validating their findings in a larger cohort of patients and investigating how AIRE mutations cause Addison’s disease.

“We have not been able to set up a functional test yet that can pinpoint what is the effect of these mutations on a functional level,” said Eriksson. “That would be the next step, I guess, because that's what we would need to do in order to answer the question, ‘how is this function altered?’” said Eriksson.


Reference

1. Eriksson, D. et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat. Comms. 959 (12). (2021).

2. Sævik, A.B. et al. Residual corticosteroid production in Autoimmune Addison’s Disease. J. Endocrinol. Metab. 105 (7): 2430-2441. (2020).

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