scholarly journals Microsatellite Polymorphism of the MHC Class I Chain-Related (MIC-A and MIC-B) Genes Marks the Risk for Autoimmune Addison’s Disease

1999 ◽  
Vol 84 (10) ◽  
pp. 3701-3707 ◽  
Author(s):  
Giovanni Gambelunghe ◽  
Alberto Falorni ◽  
Mehran Ghaderi ◽  
Stefano Laureti ◽  
Cristina Tortoioli ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Absolute Risk ◽  
Central Italy ◽  
Addison’S Disease ◽  
Class I ◽  
Addison's Disease ◽  
Specific Marker ◽  
Hla Dr ◽  
Intron 1 ◽  
Hla Dr3

Abstract The major histocompatibility complex class I chain-related MIC-A and MIC-B genes are located on chromosome 6 between the histocompatibility leucocyte antigen (HLA)-B and the B-associated transcript genes. The presence of 21-hydroxylase autoantibodies is a sensitive and specific marker of autoimmune Addison’s disease. We studied the polymorphism of exon 5 of the MIC-A gene, of intron 1 of the MIC-B gene, and of HLA-DRB1, -DQA1, and -DQB1 genes in 28 autoimmune (21-hydroxylase autoantibody positive) Addison’s disease patients and in 75 healthy subjects from central Italy. The MIC-A5.1 allele was significantly more frequent in Addison’s disease patients (79%) than in healthy subjects (36%) [odds ratio (OR) = 6.52, corrected P (Pc) = 0.0015], whereas MIC-A6 was significantly reduced in affected subjects (15% vs. 56%, OR = 0.13, Pc = 0.002). The A5.1/A5.1 genotype had an OR for autoimmune Addison’s disease as high as 18.0 and an absolute risk of 1 per 1131. In the presence of MIC-A5.1, MICB-CA-25 was significantly increased in Addison’s disease patients (25% vs. 4%, OR = 8.0, P = 0.0039, Pc = 0.047). The MICB-CA-17 allele was absent in Addison’s disease patients, but present in more than 25% healthy individuals (OR = 0.10, P = 0.0025, Pc = 0.03). Among HLA-DR and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) was significantly more frequent in Addison’s disease patients than in healthy subjects, but only in the presence of MIC-A5.1. The frequency of MIC-A5.1 was significantly increased in Addison’s disease patients only in the presence of HLA-DR3-DQ2. Our study demonstrates that susceptibility to autoimmune Addison’s disease is linked to the MIC-A microsatellite allele 5.1 and that both MIC-A5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk for Addison’s disease.

scholarly journals A high-sensitivity test in the assessment of adrenocortical insufficiency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufficiency

1998 ◽  
Vol 159 (2) ◽  
pp. 275-280 ◽  
Author(s):  
JG Gonzalez-Gonzalez ◽  
NE De la Garza-Hernandez ◽  
LG Mancillas-Adame ◽  
J Montes-Villarreal ◽  
JZ Villarreal-Perez
Keyword(s):  
Healthy Subjects ◽  
Low Dose ◽  
Standard Dose ◽  
Addison’S Disease ◽  
High Sensitivity ◽  
Serum Cortisol ◽  
Dose Assessment ◽  
Addison's Disease ◽  
Acth Test ◽  
Adrenocortical Insufficiency

The short cosyntropin (synthetic ACTH) test is recognized as the best screening manoeuvre in the assessment of adrenocortical insufficiency. Recent data, however, suggest that i.v. administration of 250 microg cosyntropin could be a pharmacological rather than a physiological stimulus, losing sensitivity for detecting adrenocortical failure. Our objective was to compare 10 vs 250 microg cosyntropin in order to find differences in serum cortisol peaks in healthy individuals, the adrenocortical response in a variety of hypothalamic-pituitary-adrenal axis disorders and the highest sensitivity and specificity serum cortisol cut-off point values. The subjects were 83 healthy people and 37 patients, the latter having Addison's disease (11), pituitary adenomas (7), Sheehan's syndrome (9) and recent use of glucocorticoid therapy (10). Forty-six healthy subjects and all patients underwent low- and standard-dose cosyntropin testing. In addition, 37 controls underwent the low-dose test. On comparing low- and standard-dose cosyntropin testing in healthy subjects there were no statistical differences in baseline and peaks of serum cortisol. In the group of patients, 2 out of 11 cases of Addison's disease showed normal cortisol criterion values during the standard test but abnormal during the low-dose test. In our group of patients and controls, the statistical analysis displayed a better sensitivity of the low-dose vs standard-dose ACTH test at 30 and 60 min. In conclusion, these results suggest that the use of 10 microg rather than 250 microg cosyntropin i.v. in the assessment of suspicious adrenocortical dysfunction gives better results.

scholarly journals Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

2016 ◽  
Vol 174 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Katerina Simunkova ◽  
Nevena Jovanovic ◽  
Espen Rostrup ◽  
Paal Methlie ◽  
Marianne Øksnes ◽  
...  
Keyword(s):  
Physical Activity ◽  
Aerobic Capacity ◽  
Healthy Subjects ◽  
Addison’S Disease ◽  
Exercise Stress ◽  
Addison's Disease ◽  
Short Term ◽  
Maximal Aerobic Capacity ◽  
Post Exercise ◽  
Stress Dose

ObjectiveMany patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity.DesignThis was a randomized placebo-controlled, cross-over clinical trial.ParticipantsTen women with Addison's disease and 10 age-matched healthy females participated in the study.MeasurementsAll women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated.ResultsMaximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P<0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise.ConclusionsThe patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further.

scholarly journals Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations

2007 ◽  
Vol 157 (6) ◽  
pp. 757-761 ◽  
Author(s):  
Z Gombos ◽  
R Hermann ◽  
M Kiviniemi ◽  
S Nejentsev ◽  
K Reimand ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Microsatellite Markers ◽  
Disease Susceptibility ◽  
Human Leukocyte ◽  
Addison’S Disease ◽  
Class Ii ◽  
Addison's Disease ◽  
Leukocyte Antigen ◽  
Geographical Regions ◽  
Hla Dr3

ObjectiveAddison's disease is an organ-specific autoimmune disorder with a polygenic background. The aim of the study was to identify non-class II human leukocyte antigen (HLA) susceptibility genes for Addison's disease.Design and methodsAddison's disease patients from three European populations were analysed for selected HLA–DR–DQ alleles and for 11 microsatellite markers covering ∼4 Mb over the HLA region. Subjects were 69 patients with Addison's disease from Estonia (24), Finland (14) and Russia (31). Consecutively recruited healthy newborns from the same geographical regions were used as controls (269 Estonian, 1000 Finnish and 413 Russian). Association measures for HLA–DRB1, DQB1, DQA1 and 11 microsatellites between D6S273 and D6S2223 were taken. A low-resolution full-house typing was used for HLA class II genes, while microsatellite markers were studied using fluorescence-based DNA fragment sizing technology.ResultsWe confirmed that the HLA–DR3–DQ2 and the DQB1*0302–DRB1*0404 haplotypes confer disease susceptibility. In Russian patients, we also found an increase of DRB1*0403 allele, combined with DQB1*0305 allele in three out of six cases (P<0.0001). Analysis of 11 microsatellite markers including STR MICA confirmed the strong linkage in DR3–DQ2 haplotypes but DRB1*0404–DQB1*0302 haplotypes were diverse. MICA5.1 allele was found in 22 out of 24 Estonian patients, but results from Finnish and Russian patients did not support its independent role in disease susceptibility.ConclusionHLA–DRB1*0403 was identified as a novel susceptibility allele for Addison's disease. Additionally, we found no evidence of a non-class II HLA disease susceptibility locus; however, the HLA–DR3–DQ2 haplotype appeared more conserved in patient groups with high DR–DQ2 frequencies.

scholarly journals Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease

2010 ◽  
Vol 95 (10) ◽  
pp. E263-E270 ◽  
Author(s):  
Peter R. Baker ◽  
Erin E. Baschal ◽  
Pam R. Fain ◽  
Taylor M. Triolo ◽  
Priyaanka Nanduri ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Addison’S Disease ◽  
Addison's Disease ◽  
Snp Analysis ◽  
Single Nucleotide ◽  
Extreme Risk ◽  
Multiplex Families ◽  
Hla Dr3 ◽  
Population Controls

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.

scholarly journals Primary Ovarian Insufficiency in women with Addison’s disease

2021 ◽  
Author(s):  
Elinor C Vogt ◽  
Lars Breivik ◽  
Ellen C Røyrvik ◽  
Marianne Grytaas ◽  
Eystein S Husebye ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Normal Population ◽  
Hormone Replacement ◽  
Addison’S Disease ◽  
Primary Ovarian Insufficiency ◽  
Addison's Disease ◽  
Specific Marker ◽  
Prescription Database ◽  
Ovarian Insufficiency ◽  
Genetic Characteristics

Abstract Context Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison’s disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. Objective To assess the prevalence of POI in a large cohort of AAD women and describe clinical, immunological, and genetic characteristics. Design and settings An observational population-based cohort study of The Norwegian National Addison Registry. The Norwegian Prescription Database (NorPD) was used to assess prescription of menopausal hormone replacement therapy (HRT). Patients A total of 458 women with AAD were studied. Main outcome measures The primary outcome was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism (SNP) variation. Results The prevalence of POI was 10.2% (47/458) and one third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). Conclusion One in ten AAD women have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing AAD women &lt; 40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC.

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