ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 8.10 | DOI: 10.1530/ey.18.8.10

Nat Commun. 2021 Feb 11;12(1):959.

The authors report a genome-wide association study (GWAS) of autoimmune Addison’s disease (AAD) in 1223 cases (defined as autoimmune adrenal failure plus positive serum autoantibodies against 21-hydroxylase) and 4097 healthy controls. Patients with APS-1 were identified and excluded. They identified 9 genome-wide significant genomic loci and explained 35–41% of the additive genetic heritability of AAD.

Autoimmune Addison’s disease (AAD) is the most common cause of primary adrenal failure in the Western world. It requires lifelong steroid hormone replacement therapy and is fatal if untreated. Autoimmunity is often apparent from the presence of other associated autoimmune diseases, and is confirmed by the presence of autoantibodies against the adrenal enzyme, 21-hydroxylase.

Besides the major risk locus at the HLA region, they identified risk variants in or near: PTPN22, CTLA4, LPP, BACH2, SH2B3, SIGLEC5, UBASH3A, and AIRE. Of these, in 5 loci an association has previously been described (PTPN22, CTLA4, HLA, AIRE, and BACH2), while 4 loci were novel (LPP, SH2B3, SIGLEC5, and UBASH3A). Of note, they found AAD associations with two LD-independent protein-coding variants in AIRE: one novel (rs74203920) and one previously reported (rs2075876) (1). These associations underline the importance of AIRE expression to maintain immune tolerance. The authors offer the interesting example of Down syndrome, where AIRE gene duplication potentially leads to altered expression in the thymus (affecting homeostasis and function of thymic epithelial cells that affect thymic selection processes), impaired central tolerance and increased risks of autoimmune diseases (2). This study also identified risk loci in genes involved in antigen presentation and recognition, and hence in thymocyte maturation.

The authors hypothesize that AAD with positive 21-hydroxylase antibodies has a rather homogenous disease etiology with relatively low polygenicity compared to other diseases, explaining at least in part the high heritability estimates (3). The study highlights the importance of the complex network of antigen presentation and immunomodulation that underlie autoimmune disease development. These findings underscore the importance of future studies in identifying and developing preventive treatment strategies.


1. Eriksson D, et al. Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison’s disease in Sweden. Sci Rep. 2018; 8(1): 8395.2. Skogberg G, et al. Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype. J Immunol. 2014; 193(5): 2187–2195.3. Skov J, et al. Heritability of Addison’s disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins. Endocrine. 2017; 58(3): 521–527.

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