Endocrine Abstracts (2009) 20 S9.2

Genetics of autoimmune Addison's disease

Simon Pearce

Institute of Human Genetics, Newcastle, UK.

Autoimmune Addison’s disease (AAD) can be divided into two distinct genetic aetiologies. The childhood onset type 1 polyendocrinopathy (aka APECED) syndrome is a monogenic autosomal recessive trait. Whereas the common-or-garden AAD that may be found as an isolated endocrinopathy, or in association with thyroid disease or type 1 diabetes as part of the autoimmune polyendocrinopathy type 2 syndrome (APS2). Isolated AAD (IAD) and APS2 can be considered as very similar from the genetic standpoint, and are inherited as complex multigenic conditions. Importantly, although families with more than one case of IAD/APS2 in them are rare, they have been found and allow an estimate for the heritability (lambda-sib) of IAD/APS2 of about 150. This means IAD/APS2 has a very strong genetic load, but that the disease alleles are likely to be rather rare in the population. Thus far, the major susceptibility loci for IAD/APS2 have been uncovered by studying candidate genes for the commoner complex autoimmune endocrinopathies such as type 1 diabetes or autoimmune thyroid disease. For instance, there are IAD/APS2 susceptibility alleles within the MHC region of chromosome 6p21, CTLA4 (2q33) and PTPN22 (1p13). Additional loci that have come to light in recent years include CYP27B1, FCRL3 and CIITA. However, none of these loci have strong effects and so none are helpful for diagnostic or predictive use in clinical practice. This is a marked contrast to the situation with APS1, where the mutational spectrum is well-defined in several populations and analysis has particular clinical utility in many circumstances.

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