Dominant suppression of Addison's disease associated with HLA-B15

Abstract

Context: 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. Design, Setting, and Participants: 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). Main Outcome Measure(s): 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 isoneof themostdramatic 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. Copyright © 2011 by The Endocrine Society.