| 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. |
- Husebye, E. S., et al.
(författare)
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Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency
- 2014
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:2, s. 104-115
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Forskningsöversikt (refereegranskat)abstract
- Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.
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| 3. |
- Sævik, Åse Bjorvatn, et al.
(författare)
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Clues for early detection of autoimmune Addison's disease : myths and realities
- 2018
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell Publishing Inc.. - 0954-6820 .- 1365-2796. ; 283:2, s. 190-199
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce.Objective: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD.Material and methods: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values.Results: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001).Conclusion: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.
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| 4. |
- Eriksson, D, et al.
(författare)
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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
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