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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
(2011) J Clin Endocrinol Metab 96: 2154-62
MeSH Terms: Addison Disease, Adult, Alleles, Autoantibodies, Female, Genetic Predisposition to Disease, Genotype, HLA-B Antigens, HLA-B15 Antigen, Haplotypes, Humans, Male, Polymorphism, Single Nucleotide, Steroid 21-Hydroxylase
Show Abstract · Added March 29, 2019
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.
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Haplotype analysis discriminates genetic risk for DR3-associated endocrine autoimmunity and helps define extreme risk for Addison's disease.
Baker PR, Baschal EE, Fain PR, Triolo TM, Nanduri P, Siebert JC, Armstrong TK, Babu SR, Rewers MJ, Gottlieb PA, Barker JM, Eisenbarth GS
(2010) J Clin Endocrinol Metab 95: E263-70
MeSH Terms: Addison Disease, Adult, Autoimmune Diseases, Autoimmunity, DNA Mutational Analysis, Endocrine Cells, Female, Gene Frequency, Genetic Predisposition to Disease, HLA-B8 Antigen, HLA-DR3 Antigen, Haplotypes, Humans, Linkage Disequilibrium, Male, Pedigree, Polymorphism, Single Nucleotide, Risk
Show Abstract · Added March 29, 2019
CONTEXT - Multiple autoimmune disorders (e.g. Addison's disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease.
OBJECTIVE - The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison's disease (AD).
DESIGN, SETTING, AND PARTICIPANTS - Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34.
MAIN OUTCOME MEASURES - AD and genotype were measured.
RESULT - Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10(-4)) and 13% of general population controls (P = 3.00 × 10(-19)). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10(-191)). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10(-5)) and type 1 diabetes patients (73%, P = 1.93 × 10(-3)). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A.
CONCLUSION - Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype.
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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
(2009) J Clin Endocrinol Metab 94: 4517-23
MeSH Terms: Addison Disease, Alleles, Autoantibodies, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Disease Progression, Genotype, Graves Disease, HLA-DQ Antigens, HLA-DQ beta-Chains, HLA-DR Antigens, HLA-DRB1 Chains, Histocompatibility Antigens Class I, Homozygote, Humans, Interferon-alpha, Microsatellite Repeats, Polymerase Chain Reaction, Polymorphism, Genetic, Risk Factors, Steroid 21-Hydroxylase
Show Abstract · Added March 29, 2019
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.
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