Genetics of the autoimmune polyglandular syndrome type 3 variant

Thyroid. 2010 Jul;20(7):737-43. doi: 10.1089/thy.2010.1639.


Background: Autoimmune thyroid diseases (AITD) and type 1 diabetes (T1D) are the most common autoimmune endocrine disorders. They occur frequently together in the same individual. This disease combination is denominated as autoimmune polyglandular syndrome type 3 variant (APS3v). This review aims to describe the genetic and pathological background of the syndrome. The joint susceptibility genes for AITD and T1D as well as the underlying pathogenetic mechanisms contributing to the development of autoimmunity are summarized.

Summary: Family and population studies showed that the APS3v syndrome has a strong genetic background. Whole genome and candidate gene approaches identified several gene variations that are present in both AITD and T1D. Most important common disease susceptibility genes are human leucocyte antigen (chromosome 6), cytotoxic T-lymphocyte-associated antigen 4 (chromosome 2), protein tyrosine phosphatase nonreceptor type 22 (chromosome 1), forkhead box P3 (X chromosome), and the interleukin-2 receptor alpha/CD25 gene region (chromosome 10), all of which contributing to the susceptibility to APS3v. With respect to the underlying pathogenetic mechanisms, these genes are altogether involved in the immune regulation, in particular in the immunological synapse and T-cell activation. In addition to these common genes, there are further candidate genes with joint risk for AITD and T1D, in particular the v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 gene (chromosome 12) and C-type lectin domain family 16 member A gene (chromosome 16). The latter one might be involved in pathogen recognition.

Conclusions: AITD and T1D share common susceptibility gene variants that possibly act pleiotropically as risk factors for the development of autoimmunity in APS3v. The functional consequences of the genetic variants as well as their interactions should be explored in greater detail. In particular, the functional consequences of the variants of forkhead box P3 predisposing to APS3v need to be elucidated. Finally, further large-scale genome-wide associations studies of single-nucleotide polymorphism variations capturing many thousand individual genetic profiles are warranted to identify further genes that are linked to the etiology of APS3v.

Publication types

  • Review

MeSH terms

  • Autoimmune Diseases / complications
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / physiopathology
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / genetics
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genetic Variation
  • Humans
  • Multifactorial Inheritance
  • Phenotype
  • Polyendocrinopathies, Autoimmune / epidemiology
  • Polyendocrinopathies, Autoimmune / genetics*
  • Polyendocrinopathies, Autoimmune / physiopathology*
  • Prevalence
  • Thyroid Diseases / complications
  • Thyroid Diseases / genetics