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.
BACKGROUND
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.


METHODS
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.


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


METHODS
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.
Triolo
Taylor M
TM
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Health Science Center, Aurora, CO 80045, USA.
Baschal
Erin E
EE
Armstrong
Taylor K
TK
Toews
Carrie S
CS
Fain
Pamela R
PR
Rewers
Marian J
MJ
Yu
Liping
L
Miao
Dongmei
D
Eisenbarth
George S
GS
Gottlieb
Peter A
PA
Barker
Jennifer M
JM
D000224:Addison Disease / Q000235:genetics / Q000276:immunology*; D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D018450:Disease Progression; D005838:Genotype; D006111:Graves Disease / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D018895:Microsatellite Repeats; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013255:Steroid 21-Hydroxylase / Q000276:immunology*
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; C099187:MHC class I-related chain A; D013255:Steroid 21-Hydroxylase