Homozygosity of the polymorphism MICA5.1 identifies extreme risk of progression to overt adrenal insufficiency among 21-hydroxylase antibody-positive patients with type 1 diabetes.

Triolo TM, Baschal EE, Armstrong TK, Toews CS, Fain PR, Rewers MJ, Yu L, Miao D, Eisenbarth GS, Gottlieb PA, Barker JM
J Clin Endocrinol Metab. 2009 94 (11): 4517-23

PMID: 19820007 · PMCID: PMC2775653 · DOI:10.1210/jc.2009-1308

CONTEXT - Autoimmunity associated with Addison's disease (AD) can be detected by measuring 21-hydroxylase (21OH) autoantibodies. Subjects with type 1 diabetes (T1D) are at increased risk for AD. Genetic factors including HLA-DRB1*0404 and MICA have been associated with AD in populations with and without T1D.

OBJECTIVE - The objective of the study was to examine the effect of the MICA5.1 allele in subjects with 21OH autoantibodies on progression to AD.

DESIGN - Two components were used: 1) a cross-sectional study with subjects with AD identified and enrolled from September 1993 to November 2008 and 2) a cohort study prospectively following up patients with T1D who screened positive for 21OH autoantibodies.

SETTING - Subjects were identified from the Barbara Davis Center and through the National Adrenal Diseases Foundation.

PATIENTS - Sixty-three subjects with AD were referred through the National Adrenal Diseases Foundation (AD referrals). Sixty-three subjects with positive 21OH antibodies from the Barbara Davis Center were followed up for progression to AD, and 11 were diagnosed with AD (progressors).

RESULTS - Seventy-three percent of progressors (eight of 11) and 57% of AD referrals (36 of 63) were MICA5.1 homozygous (P = ns). Overall, 59% of patients with AD (44 of 74) were MICA5.1/5.1 compared with 17% of nonprogressors (nine of 52) (P < 0.0001) and 19% of normal DR3/4-DQB1*0302 controls (64 of 336) (P < 0.0001).

CONCLUSIONS - Identifying extreme risk should facilitate monitoring of progression from 21OH antibody positivity to overt AD. The HLA-DR3/0404 genotype defines high-risk subjects for adrenal autoimmunity. MICA5.1/5.1 may define those at highest risk for progression to overt AD, a feature unique to AD and distinct from T1D.

MeSH Terms (21)

Addison Disease Alleles Autoantibodies Cross-Sectional Studies Diabetes Mellitus, Type 1 Disease Progression Genotype Graves Disease Histocompatibility Antigens Class I HLA-DQ Antigens HLA-DQ beta-Chains HLA-DR Antigens HLA-DRB1 Chains Homozygote Humans Interferon-alpha Microsatellite Repeats Polymerase Chain Reaction Polymorphism, Genetic Risk Factors Steroid 21-Hydroxylase

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