title: Dominant suppression of Addison's disease associated with HLA-B15.
abstract: BACKGROUND
  Autoimmune Addison's disease (AD) is the major cause of primary adrenal failure in developed nations. Autoantibodies to 21-hydroxylase (21OH-AA) are associated with increased risk of progression to AD. Highest genetic risk is associated with the Major Histocompatibility region (MHC), specifically human leukocyte antigen (HLA)-DR3 haplotypes (containing HLA-B8) and HLA-DR4.
  
  
  OBJECTIVE
  The objective of the study was the further characterization of AD risk associated with MHC alleles.
  
  
  METHODS
  MHC genotypes were determined for HLA-DRB1, DQA1, DQB1, MICA, HLA-B, and HLA-A in 168 total individuals with 21OH-AA (85 with AD at referral and 83 with positive 21OH-AA but without AD at referral).
  
  
  METHODS
  Genotype was evaluated in 21OH-AA-positive individuals. Outcomes were compared with general population controls and type 1 diabetes patients.
  
  
  RESULTS
  In HLA-DR4+ individuals, HLA-B15 was found in only one of 55 (2%) with AD vs. 24 of 63 (40%) 21OH-AA-positive nonprogressors (P = 2 × 10(-7)) and 518 of 1558 (33%) HLA-DR4 patients with type 1 diabetes (P = 1 × 10(-8)). On prospective follow-up, none of the HLA-B15-positive, 21-hydroxylase-positive individuals progressed to AD vs. 25% non-HLA-B15 autoantibody-positive individuals by life table analysis (P = 0.03). Single nucleotide polymorphism analysis revealed the HLA-DR/DQ region associated with risk and HLA-B15 were separated by multiple intervening single-nucleotide polymorphism haplotypes.
  
  
  CONCLUSIONS
  HLA-B15 is not associated with protection from 21OH-AA formation but is associated with protection from progression to AD in 21OH-AA-positive individuals. To our knowledge, this is one of the most dramatic examples of genetic disease suppression in individuals who already have developed autoantibodies and of novel dominant suppression of an autoimmune disease by a class I HLA allele.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045-6511, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Baker
authors.forename: Erin E
authors.initials: EE
authors.lastname: Baschal
authors.forename: Pam R
authors.initials: PR
authors.lastname: Fain
authors.forename: Priyaanka
authors.initials: P
authors.lastname: Nanduri
authors.forename: Taylor M
authors.initials: TM
authors.lastname: Triolo
authors.forename: Janet C
authors.initials: JC
authors.lastname: Siebert
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Armstrong
authors.forename: Sunanda R
authors.initials: SR
authors.lastname: Babu
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Rewers
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Barker
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000224:Addison Disease / Q000235:genetics* / Q000276:immunology; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D059910:HLA-B15 Antigen; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D015235:HLA-B Antigens; D059910:HLA-B15 Antigen; D013255:Steroid 21-Hydroxylase