HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III

J Clin Endocrinol Metab. 2014 Jan;99(1):E177-82. doi: 10.1210/jc.2013-2852. Epub 2013 Dec 20.


Background: Genetics of the adult autoimmune polyglandular syndrome (APS) is poorly understood.

Aim: The aim of this study was to gain further insight into the genetics of the adult APS types. SITE: The study was conducted at a university referral center.

Methods: The human leukocyte antigen (HLA) class II alleles, haplotypes, and genotypes were determined in a large cohort of patients with APS, autoimmune thyroid disease (AITD), and type 1 diabetes and in healthy controls by the consistent application of high-resolution typing at a four-digit level.

Results: Comparison of the allele and haplotype frequencies significantly discriminated patients with APS vs AITD and controls. The HLA class II alleles DRB1*03:01 *04:01, DQA1*03:01, *05:01, DQB1*02:01, and *03:02 were observed more frequently (P<.001) in APS than in AITD and controls, whereas the alleles DRB1*15:01, DQB1*03:01, and *06:02 were underrepresented in APS vs AITD (Pc<.001) and controls (Pc<.01), respectively. The DRB1*03:01-DQA1*05:01-DQB1*02:01 (DR3-DQ2) and DRB1*04:01-DQA1*03:01:DQB1*03:02 (DRB1*04:01-DQ8) haplotypes were overrepresented in APS (Pc<.001). Combination of both haplotypes to a genotype was highly prevalent in APS vs AITD and controls (Pc<.001). Dividing the APS collective into those with Addison's disease (APS type II) and those without Addison's disease but including type 1 diabetes and AITD (APS type III) demonstrated DR3-DQ2/DRB1*04:01-DQ8 as a susceptibility genotype in APS III (Pc<.001), whereas the DR3-DQ2/DRB1*04:04-DQ8 genotype correlated with APS II (Pc<.001). The haplotypes DRB1*11:01-DQA1*05:05-DQB1*03:01 and DRB1*15:01-DQA1*01:02-DQB1*06:02 are protective in APS III but not in type II (Pc<.01).

Conclusions: HLA class II haplotypes differentiate between the adult APS types II and III. Susceptible haplotypes favor the development of polyglandular autoimmunity in patients with AITD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Child
  • Diagnosis, Differential
  • Female
  • Gene Frequency
  • Genes, MHC Class II*
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Polyendocrinopathies, Autoimmune / classification
  • Polyendocrinopathies, Autoimmune / diagnosis*
  • Polyendocrinopathies, Autoimmune / genetics
  • Young Adult