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Nat Commun ; 12(1): 959, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574239

RESUMO

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 × 10-8). 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 × 10-25) 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 (h2).


Assuntos
Doença de Addison/genética , Estudo de Associação Genômica Ampla , Fatores de Transcrição de Zíper de Leucina Básica/genética , Antígeno CTLA-4/genética , Feminino , Humanos , Masculino , Modelos Moleculares , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Risco
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