Abstract
BackgroundAddison's disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The pathogenesis is multi-factorial, involving genetic components and hitherto unknown environmental factors. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD.MethodsA genome-wide study using the Affymetrix GeneChip® Genome-Wide Human SNP Array 6.0 was conducted in 26 patients with AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays.ResultsWe found that low copy number of UGT2B28 was significantly more frequent in AD patients compared to controls; conversely high copy number of ADAM3A was associated with AD.ConclusionsWe have identified two novel CNV associations to ADAM3A and UGT2B28 in AD. The mechanism by which this susceptibility is conferred is at present unclear, but may involve steroid inactivation (UGT2B28) and T cell maturation (ADAM3A). Characterization of these proteins may unravel novel information on the pathogenesis of autoimmunity.
Highlights
Addison’s disease (AD) is caused by an autoimmune destruction of the adrenal cortex
autoimmune polyendocrine syndromes (APS) type I is caused by mutations in the gene autoimmune regulator (AIRE), which has a function in developing immunological tolerance in the thymus
Affymetrix’ recommendations, with Median Absolute Pair wise Difference (MAPD) values ranging from 0.194-0.299 and quality control (QC) call rate ranging from 88.2-99.0%
Summary
Addison’s disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays. Primary adrenal insufficiency (Addison’s disease (AD)) is most commonly caused by an autoimmune destruction of the adrenal cortex, resulting in failure to produce corticosteroids. Isolated AD, or AD in combination with other endocrine components where APS I has been ruled out, is thought to be caused by a combination of genetic and environmental factors, and stochastic events. Other susceptibility genes are MHC-class I related chain A and B (MICA and MICB) [4,5], cytotoxic T lymphocyte
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