Autoimmune Addison's disease is the immune system's destruction of the adrenal cortex. The first genome-wide study of it found nine risk loci: immune genes it shares with other autoimmune diseases, and AIRE, a gene that teaches the immune system what not to attack.
Addison's disease, in its autoimmune form, is the destruction of the adrenal cortex by the body's own immune system, leaving the adrenal glands unable to make enough of their hormones. It is rare, and the study behind this page notes that its low prevalence and complex inheritance had long held genetic studies back.
The 2021 study was the first genome-wide association study of autoimmune Addison's disease. The GWAS Catalog records its sample as 1,223 cases and 4,097 controls of European ancestry. It identified nine independent risk loci. Several are loci the disease shares with other autoimmune conditions — HLA, BACH2, PTPN22 and CTLA4 — which fits the way autoimmune diseases cluster in the same people and families, as with type 1 diabetes and autoimmune thyroid disease.
The study's distinctive finding is two protein-coding changes in AIRE, the autoimmune regulator. AIRE works in the thymus, where developing immune cells are shown the body's own proteins so that the ones that would attack them can be removed — what the study calls central immunological tolerance. The strongest change, p.R471C (rs74203920, odds ratio 3.4), adds a cysteine to a zinc-finger region of the protein; that position is not in this catalogue. Taken together, the loci explain 35-41% of the disease's heritability.
Two of the study's positions are here. rs3998178, in the HLA region near HLA-DQB1, carries the largest effect in its records, with an odds ratio of 5.98. rs11571303, in CTLA4 — a brake on T-cell activation — has an odds ratio of 1.39.
Addison's disease is diagnosed by a clinician with blood tests of adrenal function — not from a genotype. Neither of the two variants on this page is used by any guideline to predict, screen for or diagnose it.
The symptoms of adrenal insufficiency — tiredness, weight loss, low blood pressure, salt craving, darkening of the skin — develop slowly and are easy to miss, and a sudden worsening can be an emergency. Anyone with those symptoms, or with a diagnosis and a question about their treatment, should speak to a clinician; treatment replaces the missing hormones and is managed by them. Carrying a risk allele at HLA or CTLA4 is common and says little on its own about any one person.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Addison's Disease comes down to these specific, well-studied positions — not a diagnosis.
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Addison's Disease. MyGeneLog™. https://www.mygenelog.com/conditions/addisons-disease
Addison's disease is a failure of the adrenal glands to make enough of their hormones. In its autoimmune form, the body's own immune system destroys the adrenal cortex.
Partly. The first genome-wide study found nine risk loci, several shared with other autoimmune diseases, and together they explain 35-41% of its heritability.
The two positions here are near HLA-DQB1, in the HLA region, and in CTLA4. The study also highlights AIRE, a gene for immune tolerance, whose position is not in this catalogue.
No. They are population-level findings, and no guideline uses them to predict the disease. It is diagnosed with blood tests of adrenal function, by a clinician.
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