Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
Nat Commun. 2021 Feb 11;12(1):959. doi: 10.1038/s41467-021-21015-8.
Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h).
自身免疫性肾上腺皮质功能减退症（AAD）的特征是肾上腺皮质的自身免疫破坏。低患病率和复杂的遗传一直阻碍了成功的遗传研究。我们在此报告了第一项针对 AAD 的全基因组关联研究，该研究确定了九个独立的风险位点（P < 5×10）。除了与其他自身免疫性疾病（如 HLA、BACH2、PTPN22 和 CTLA4）共享的涉及淋巴细胞功能和发育的位点外，我们还将自身免疫调节剂（AIRE）中的两个蛋白编码改变与 AAD 相关联。最强的是 p.R471C（rs74203920，OR = 3.4（2.7-4.3），P = 9.0×10），在 AIRE 蛋白第二个 PHD 结构域的锌指结构域中引入了一个额外的半胱氨酸残基。这种对 AAD 发病机制遗传贡献的无偏阐明表明了中枢免疫耐受的重要性，并解释了 35-41%的遗传率（h）。
