A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans

López, Ernesto; Zwermann, Oliver; Segni, Maria; Meyer, Gesine; Reincke, Martín; Seißler, Jochen; Herwig, J.; Usadel, K. H.; Badenhoop, Klaus

doi:10.1530/eje.0.1510193

Cited by 105 publications

(67 citation statements)

References 26 publications

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“…In contrast, two recent small studies have shown association of CYP27B1 promoter alleles within trio families with Type 1 diabetes (Lopez et al 2004a) and in a case-control design in cohorts of patients with Addison's disease, GD, Hashimoto's thyroiditis and Type 1 diabetes from the German population (Lopez et al 2004b). Replication of these findings in an independent patient cohort would be an important step forward in confirming these potentially exciting findings.…”

Section: Introductionmentioning

confidence: 94%

A haplotype of the CYP27B1 promoter is associated with autoimmune Addison’s disease but not with Graves’ disease in a UK population

Jennings

Owen²,

Wilson³

et al. 2005

Journal of Molecular Endocrinology

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Previous studies have suggested an association between alleles of the CYP27B1 (1-hydroxylase) gene and autoimmune conditions. We have examined three single nucleotide polymorphisms (SNPs) that are located in the 58 region and promoter of the CYP27B1 gene for association in a cohort of Graves' disease and autoimmune Addison's disease subjects from the UK. Genomic DNA samples from white patients with autoimmune Addison's disease (n=104) and healthy controls (n=464) were genotyped by PCR-RFLP analysis for the SNPs at positions −1918, −1260 and −1077 58 of the coding CYP27B1 sequences. The −1260 SNP was also examined in a cohort of patients with Graves' disease (n=446).2 testing of contingency tables was used to determine the significance of genotypes and alleles. Haplotype frequencies and linkage disequilibrium measures were estimated using the UNPHASED and HAPLOVIEW packages. Alleles at the three CYP27B1 markers were in tight linkage disequilibrium with each other and all showed association with autoimmune Addison's disease. The maximum evidence for association was with the −1260 C allele (76·0% in Addison's subjects versus 64·9% in controls; P=0·003; odds ratio 1·71 (5-95% confidence intervals, 1·20-2·44). A global test of significance for the common −1918 T, −1260 C and −1077 G haplotype was significant in Addison's subjects compared with controls (P=0·01). In contrast, there was no association of alleles at the −1260 SNP with Graves' disease. We are able to confirm that a CYP27B1 promoter allele is associated with autoimmune Addison's disease, and extend this finding to include an associated promoter haplotype.

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Section: Introductionmentioning

confidence: 94%

A haplotype of the CYP27B1 promoter is associated with autoimmune Addison’s disease but not with Graves’ disease in a UK population

Jennings

Owen²,

Wilson³

et al. 2005

Journal of Molecular Endocrinology

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“…Moreover, polymorphisms of the CYP27B1 hydroxylase gene catalyzing the conversion of 25 hydroxyvitamin D 3 (25(OH)D) to its active form were also associated with HT (69). Vitamin D levels were associated with VDR and vitamin D level-related genetic variants (70,71).…”

Section: The Role Of Vitamin D Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Thyroid and polycystic ovary syndrome

Gaberšček

Zaletel

Schwetz

et al. 2015

European Journal of Endocrinology

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Thyroid disorders, especially Hashimoto's thyroiditis (HT), and polycystic ovary syndrome (PCOS) are closely associated, based on a number of studies showing a significantly higher prevalence of HT in women with PCOS than in controls. However, the mechanisms of this association are not as clear. Certainly, genetic susceptibility contributes an important part to the development of HT and PCOS. However, a common genetic background has not yet been established. Polymorphisms of the PCOS-related gene for fibrillin 3 (FBN3) could be involved in the pathogenesis of HT and PCOS. Fibrillins influence the activity of transforming growth factor beta (TGFb). Multifunctional TGFb is also a key regulator of immune tolerance by stimulating regulatory T cells (Tregs), which are known to inhibit excessive immune response. With lower TGFb and Treg levels, the autoimmune processes, well known in HT and assumed in PCOS, might develop. In fact, lower levels of TGFb1 were found in HT as well as in PCOS women carrying allele 8 of D19S884 in the FBN3 gene. Additionally, vitamin D deficiency was shown to decrease Tregs. Finally, high estrogen-to-progesterone ratio owing to anovulatory cycles in PCOS women could enhance the immune response. Harmful metabolic and reproductive effects were shown to be more pronounced in women with HT and PCOS when compared with women with HT alone or with controls. In conclusion, HT and PCOS are associated not only with respect to their prevalence, but also with regard to etiology and clinical consequences. However, a possible crosstalk of this association is yet to be elucidated.

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“…Diverse genetic variations predispose to autoimmune AD (20,21,22). Most of them are susceptibility factors for autoimmunity in general.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Increasing prevalence of Addison's disease in German females: health insurance data 2008–2012

Meyer

Neumann

Badenhoop

et al. 2014

European Journal of Endocrinology

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Objective: Our objective was to investigate the epidemiology of autoimmune Addison's disease (AD) in Germany. Design: Routine data were analyzed from the Statutory Health Insurance (SHI) database of the Techniker Krankenkasse (TK) for an observation period from 01/01/2008 to 31/12/2012. The TK is one of the largest German health care insurance providers covering more than 10% of the German population. Subjects and methods: Between 2008 and 2012, a total of 2477 diagnoses of primary adrenal failure were recorded in the SHI database. After exclusion of secondary, iatrogenic or other non-idiopathic forms and after adjustment for incomplete data sets, 1364 diagnoses of autoimmune-mediated AD remained. Results: The prevalence of AD in our cohort showed a steady increase from 82 per million in 2008 to 87 per million in 2012. On average, the prevalence rose about 1.8% per year, and due to a pronounced increase (2.7%) in females. The prevalence was lower in men (63-68 per million) than in women (96-108 per million). Autoimmune comorbidities were found in 46.5% of AD patients. Adrenal crises were documented with a frequency of 14-17/100 patient years. Conclusions: These data provide a first epidemiological profile of this rare and perilous endocrine disease in Germany. Although the prevalence of AD appears lower than in the Scandinavian countries, the increasing figures in females over the last 5 years warrant further investigations. Furthermore, adrenal crises pose a considerable burden. Hereby, we can show that health insurance data provide a valuable tool for epidemiological studies in the absence of national registries.

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A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans

Cited by 105 publications

References 26 publications

A haplotype of the CYP27B1 promoter is associated with autoimmune Addison’s disease but not with Graves’ disease in a UK population

A haplotype of the CYP27B1 promoter is associated with autoimmune Addison’s disease but not with Graves’ disease in a UK population

MECHANISMS IN ENDOCRINOLOGY: Thyroid and polycystic ovary syndrome

Increasing prevalence of Addison's disease in German females: health insurance data 2008–2012

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