| 1. |
- Lobell, Anna, et al.
(författare)
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Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
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| 2. |
- Bjornsdottir, Sigridur, et al.
(författare)
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Drug Prescription Patterns in Patients With Addison's Disease : A Swedish Population-Based Cohort Study
- 2013
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:5, s. 2009-2018
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Tidskriftsartikel (refereegranskat)abstract
- Context: There are no published data on drug prescription in patients with Addison's disease ( AD). Objective: Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. Design and Setting: We conducted a population-based cohort study in Sweden. Patients: Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. Main Outcome Measure: We determined the ratio of observed to expected number of patients treated with prescribed drugs. Results: Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. Conclusion: Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.
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| 3. |
- Bothou, Christina, et al.
(författare)
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Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency : Experience from a Multicenter Survey
- 2020
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 105:8
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Tidskriftsartikel (refereegranskat)abstract
- Context: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment.Objective: Multicenter survey on current clinical approaches in managing AI during pregnancy.Design: Retrospective anonymized data collection from 19 international centers from 2013 to 2019.Setting and patients: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%).Results: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes.Conclusions: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.
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| 4. |
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| 5. |
- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.
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| 6. |
- Eriksson, Daniel, et al.
(författare)
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Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison’s disease in Sweden
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
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| 7. |
- Eriksson, Daniel, et al.
(författare)
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Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
- 2018
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:1, s. 179-186
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Tidskriftsartikel (refereegranskat)abstract
- Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
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| 8. |
- Eriksson, Daniel, et al.
(författare)
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GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).
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| 9. |
- Landegren, Nils, et al.
(författare)
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Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1
- 2016
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.
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| 10. |
- Lundtoft, Christian, et al.
(författare)
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Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease.
- 2023
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Ingår i: European journal of endocrinology. - : Bioscientifica. - 1479-683X .- 0804-4643. ; 189:2, s. 235-241
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD.Case-control study on patients with AAD and healthy controls.Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls.With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10-44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 × 10-63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD.We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.
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