Association of genetic polymorphisms and autoimmune Addison’s disease

Abstract

Autoimmune Addison's disease (AAD) is a complex genetic disease that results from the interaction of a predisposing genetic background with as yet unknown environmental factors. The disease is marked by the appearance of circulating autoantibodies against steroid 21-hydroxylase. Mutations of the autoimmune regulator gene are responsible for the so-called autoimmune polyendocrine syndrome type I (APS I), of which AAD is a major disease component. Among genetic factors for isolated AAD and APS II, a major role is played by HLA class II genes: HLA-DRB1 0301-DQA1 0501-DQB1 0201 and DRB1 04-DQA1 0301-DQB1 0302 are positively, and RB1 0403 is negatively, associated with a genetic risk for AAD. The MHC class I chain-related gene A allele 5.1 is strongly and positively associated with AAD. Other gene polymorphisms contributing to genetic risk for AAD are MHC2TA, the gene coding for class II transactivator, the master regulator of class II expression, cytotoxic T lymphocyte antigen-4, PTPN22 and the vitamin D receptor.

Autoantibody responses in autoimmune ovarian insufficiency and in Addison's disease are IgG1 dominated and suggest a predominant, but not exclusive, Th1 type of response

“…Genetic predisposition for AAD is modulated by polymorphisms of genes influencing the function of the immune system, such as HLA class II genes, CTLA4, CIITA, PTPN22, and others (10). Though 17OHAb and P450sccAb can be detected in a fraction of patients with AAD, these markers are more frequently present in sera from patients with autoimmune polyendocrine syndrome type 1 (APS1) or in women with adrenal insufficiency and autoimmune oophoritis (1,2,11,12).…”

Autoimmunity to Steroid-Producing Cells

“…The CTLA-4 gene polymorphism and the PTPN22 gene polymorphism have been found to modulate genetic risk for AAD (Falorni et al, 2008;Skinningsrud et al, 2008a). A recent metanalysis of European studies has confirmed that the CTLA-4 Ala 17 polymorphism is strongly associated with genetic risk for AAD, independentenly from the well known association with the polymorphism of HLA class II genes (Brozzetti et al, 2010b).…”

“…Outside APS1, AAD shares many predisposing genetic factors with other endocrine autoimmune diseases that are components of APS2, such as thyroid autoimmune diseases and T1DM, the major genetic markers associated with the diseases beeing located in the HLA region on chromosome 6. The disease is strongly and positively associated with both HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) (Falorni et al, 2008). The HLA-DRB1*01-DQA1*01-DQB1*0501 and DRB1*13-DQA1*0103-DQB1*0603 haplotypes are negatively associated with genetic risk for AAD.…”

Autoanticorpi anti-surrene nell’insufficienza corticosurrenalica primitiva

“…I principali marcatori genetici di predisposizione per lo sviluppo della malattia sono localizzati nella regione HLA, sul cromosoma 6. Infatti, MAA è positivamente associata con HLA-DRB1 * 0301-DQA1 * 0501-DQB1 * 0201 (DR3-DQ2) e DRB1 * 04-DQA1 * 0301-DQB1 * 0302 (DR4-DQ8) [22]. HLA-DRB1 * 01-DQA1 * 01-DQB1 * 0501 e DRB1 * 13-DQA1 * 0103-DQB1 * 0603 sono invece negativamente associati con lo sviluppo di MAA.…”

“…Tra i geni non-HLA, i polimorfismi di CTLA-4 e di PTPN22 contribuiscono al rischio per lo sviluppo di MAA e di altre malattie endocrine autoimmuni [22,[28][29][30]. Due studi europei indipendenti hanno documentato l'associazione del gene del transattivatore delle molecole HLA di classe II (CIITA, MHC2TA) con MAA [31,32].…”