title: HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III.
abstract: BACKGROUND
  Genetics of the adult autoimmune polyglandular syndrome (APS) is poorly understood.
  
  
  OBJECTIVE
  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.
authors.affiliation: Laboratory of Immunogenetics/HLA (B.K.F., C.W.), German Red Cross Blood Service West, Bad Kreuznach 55543, Germany; Molecular Thyroid Research Laboratory (N.M., G.J.K.), Johannes Gutenberg University Medical Center, Mainz 55101, Germany; Bioinformatics Unit (T.A.) and Center for Transfusion Medicine (J.B.), German Red Cross Blood Service West, Hagen 58097, Germany.
authors.forename: B K
authors.initials: BK
authors.lastname: Flesch
authors.forename: N
authors.initials: N
authors.lastname: Matheis
authors.forename: T
authors.initials: T
authors.lastname: Alt
authors.forename: C
authors.initials: C
authors.lastname: Weinstock
authors.forename: J
authors.initials: J
authors.lastname: Bux
authors.forename: G J
authors.initials: GJ
authors.lastname: Kahaly
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D005787:Gene Frequency; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000145:classification / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult