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

Baker PR, Baschal EE, Fain PR, Nanduri P, Triolo TM, Siebert JC, Armstrong TK, Babu SR, Rewers MJ, Gottlieb PA, Barker JM, Eisenbarth GS
J Clin Endocrinol Metab. 2011 96 (7): 2154-62

PMID: 21565792 · PMCID: PMC3135206 · DOI:10.1210/jc.2010-2964

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 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.

MeSH Terms (14)

Addison Disease Adult Alleles Autoantibodies Female Genetic Predisposition to Disease Genotype Haplotypes HLA-B15 Antigen HLA-B Antigens Humans Male Polymorphism, Single Nucleotide Steroid 21-Hydroxylase

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