Background: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor. Materials and Methods: Patients with type 1 diabetes (n ¼ 220), Hashimoto's thyroiditis (n ¼ 94), Addison's disease (n ¼ 121) and healthy controls (n ¼ 239) were genotyped for the gene polymorphism PTPN22 1858 C/T. Results: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P ¼ 0.0009; odds ratio for allele T ¼ 1.88, 95% confidence interval [1.3 -2.7]). Furthermore, we found a strong association in female patients with T1D (P ¼ 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto's thyroiditis or Addison's disease and healthy controls. Conclusion: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.
endocrine regulator [ 5 ] . The active form of VD, 1α,25(OH) 2 D or calcitriol, is synthesised from precursor cholesterol by metabolic steps in skin, liver, and kidney. The primary metabolite, 25OHD, is the most abundant form of VD in blood and therefore established for measuring VD status. Various studies have shown an association of VD status and T2D [ 6 ] . Low 25OHD is found more often in patients with T2D [ 7 , 8 ] and correlates with a higher risk for T2D [ 6 , 9 , 10 ] . Furthermore, the 25OHD serum concentration is negatively associated with components of the metabolic syndrome, such as obesity, hyperglycaemia [ 11 -13 ] , and high body mass index (BMI) [ 9 , 14 -16 ] . Finally, many studies confi rmed an inverse correlation between 25OHD and parameters of insulin resistance: fasting glucose, glucose tolerance, insulin levels, and homeostasis model assessment-index (HOMA-I) [ 17 -24 ] . In addition, interventional studies showed benefi cial eff ects of VD on glucose status, insulin sensitivity, and insulin resistance [ 25 -27 ] . Introduction ▼According to the International Diabetes Federation, more than 300 million people worldwide are currently aff ected by diabetes mellitus ( http://www.idf.org/diabetesatlas/5e/the-globalburden ). A further increase of diabetes prevalence is expected, in particular due to the growing population in developing countries, the increasing industrialisation, urbanisation, and life style changes [ 1 , 2 ] . Diabetes pathophysiology is believed to result from environmental factors on a genetic background, but the causal genes remain complex and exert low hazard risk ratios [ 3 ] . The prevalence of type 2 diabetes (T2D) is infl uenced by multiple environmental factors, one of them may lie in the vitamin D system [ 4 ] . During recent years, vitamin D (VD), mainly known for its eff ects on bone and mineral metabolism, is growingly perceived as a pleiotropic
Vitamin D has been involved in the modulation of calcium and bone metabolism as well as in the immune system, where it suppresses the proliferation of activated T cells. These effects are exerted via the vitamin D receptor (VDR). Polymorphisms within this gene have been exhaustively studied in diverse autoimmune diseases but with inconsistent results. We previously reported a positive association of polymorphisms within the VDR gene (Apa I, Taq I, Bsm I, and Fok I). In the present article we extended our previous reports to seven additional polymorphisms (rs757343, rs9729, rs2853559, rs1989969, rs3847987, rs2238135, and rs4516035) in a larger set of German simplex type 1 diabetes families. Additionally we correlated serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) with VDR genotypes and haplotypes. The haplotypes "CG" (Taq I-Apa I), "CGG" (Taq I-Apa I-Tru I), "CGC" (Taq I-Apa I-Fok I), "GCTG" (rs9729-Taq I-Apa I-Tru I), and "CGGC"(Taq I-Apa I, Tru I, Fok I) were less often transmitted, thus negatively associated with type 1 diabetes. Patients who carried the genotype "CC" of the rs3847987 polymorphism had higher median serum levels of 25(OH)D(3). Furthermore, the majority of patients with this genotype possessed normal serum levels of 25(OH)D(3). We conclude that variants of the VDR may confer a genetic protection from type 1 diabetes. Furthermore, normal serum levels of 25(OH)D(3) appear to correlate with a VDR genotype. This supports a role of vitamin D in the immune pathogenesis of type 1 diabetes.
A higher risk for DTC is conferred by haplotypes within the CYP24A1 gene, low circulating 25(OH)D(3) levels (deficiency), and a reduced conversion to 1,25(OH)(2)D(3). These results confirm and extend previous observations and also support a role of the vitamin D system in the pathogenesis of DTC. How deficient 25(OH)D(3) levels in combination with certain CYP24A1 haplotypes affect vitamin D activation is the subject of future studies.
BackgroundGene 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.AimTo investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.MethodsA 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.ResultsWe 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-κB1 and IL23A genes in the UK and Italian cohorts respectively.ConclusionsVariants 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.
Vitamin D is a secosteroid hormone that resembles other nuclear steroid hormones such as thyroid, gluco-, and mineralocorticoids, as well as gonadal effector systems. Primarily understood as a master regulator of bone and calcium/phosphate physiology, it is now increasingly recognized as orchestrating numerous aspects of cell growth and differentiation in many tissues, including those of innate and acquired immunity. This review addresses recently discovered aspects that highlight vitamin D's potential for immune intervention and how the vitamin D pathway is utilized for anti-infective and antineoplastic immunity. This provides the rationale for novel therapeutic strategies in the context both of prevention and of therapy of immune dysregulation in type 1 diabetes.
We investigated effects of the first orally active atriopeptidase inhibitor UK 79300 (Pfizer Clinical Research, UK) on left ventricular hydraulic load in patients with congestive heart failure NYHA II and III. In our study, 6 patients received 200 mg and 4 patients received 400 mg of UK 79300, and 4 patients received placebo (controls). Before and 90 min after oral administration of UK 79300 or placebo aortic input impedance was assessed to characterize left ventricular hydraulic load. Plasma levels of atrial natriuretic peptide (ANP) significantly increased by 126% after 200 mg and by 141% after 400 mg of UK 79300, but remained unchanged in control patients. Mean arterial pressure and flow, resistive term, characteristic impedance and oscillatory aortic input pressure power showed minor changes without statistical significance on an intergroup comparison. We conclude that acute atriopeptidase inhibition by UK 79300 effectively increases endogenous ANP levels up to 2.5-fold. However, these changes were not accompanied by significant effects on left ventricular hydraulic load.
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