Sub-Areas to Risk Factors and Susceptibility:
(Journal Article): Elimination of Dietary Gluten and Development of Type 1 Diabetes in High Risk Subjects
Fuchtenbusch M, Ziegler AG, Hummel M (Diabetes Research Institute, Koelner Platz 1, 80804 Munich, Germany,
michael.hummel(at)lrz.uni-muenchen.de
)
IN:
Rev Diabetic Stud
2004; 1(1):39-41
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)
ABSTRACT: Removal of dietary gluten is associated with a lower frequency of type 1 diabetes (T1D) in patients with celiac disease. Therefore, we performed a pilot study in which seven islet-antibody-positive first degree relatives of patients with T1D were placed on a gluten-free diet for 12 months, followed by gluten re-exposure for 12 months, to investigate whether this could reduce levels of circulating autoantibodies. We found that islet autoantibody levels at the end of the gluten-free period were not different to those before the commencement of the diet nor to antibody levels at the end of the gluten re-exposure period. In the present study, we have followed the 7 children formerly placed on a gluten-free diet for the manifestation of T1D for up to 5 years (mean follow-up time after fulfilling inclusion criteria: 4.8 years, SE 0.82 years) and compared them to 30 siblings and offspring of patients with T1D with similar characteristics to the intervention group (mean follow-up time: 5 years, SE 0.62 years). The cumulative 5-year risk of T1D in the inter-vention group did not differ from that in the prediabetic control group (42.9%, 95 CI [6.3 – 79.5%] vs. 49.7%, 95 CI [30.9 – 68.5%], p=0.87, log-rank test). These findings sug-gest that removing gluten from the diet over a period of one year is effective neither in the short nor in the long term in high-risk prediabetic individuals with a fully activated im-mune response to different islet antigens close to manifestation of T1D. These and recent data showing that exposure to dietary gluten in offspring of mothers and fathers with T1D very early in life is associated with an increased risk of developing islet antibodies also suggest that removal of dietary gluten should be tested as early as possible in chil-dren with an increased risk of islet autoimunity, i.e. before an immune response to islet antigens is established.
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(Journal Article): Relation between the tumor necrosis factor-alpha (TNF-alpha) gene and protein expression, and clinical, biochemical, and genetic markers: age, body mass index and uric acid are independent predictors for an elevated TNF-alpha plasma level in a complex risk model
Schulz S, Schagdarsurengin U, Suss T, Mller-Werdan U, Werdan K, Glaser C (Institute of Human Genetics and Medical Biology Department of Medicine III, Martin-Luther-Universitat Halle-Wittenberg)
IN:
Eur Cytokine Netw
2004; 15(2):105-111
Impact Factor(s) of Eur Cytokine Netw: 1.747 (2004), 2.153 (2002), 1.677 (2001)
Fulltext: HTML
ABSTRACT: Background: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of numerous complex diseases. The plasma level of this pro-inflammatory cytokine is associated with a variety of different risk factors, but little is known about the genetic background and the complex interactions. Methods: in this clinical study, correlations were studied between plasma levels of circulating TNF-alpha protein (ELISA), its mRNA expression in monocytes (RT-PCR) and genetic variants of TNF-alpha gene (SSCP), with several diseases, including obesity, atherosclerosis, diabetes mellitus, hypertension, as well as risk factors such as age, gender, inflammatory markers, the coagulation\fibrinolysis balance, and lipid metabolism. One hundred and ninety four clinically and biochemically well-characterized patients were enrolled. Results: At the transcriptional level, measured in monocytes, no association with any clinical or biochemical parameter investigated was found, including TNF-alpha protein level. Investigating the influence of genetic variants of the TNF-alpha gene on mRNA and protein levels, only one promoter polymorphism, namely c.-238G > A, was shown to be associated with transcriptional but not with translational expression. However, at the translational level, significant positive, but weak associations were determined for obesity (P -/+ 0.037), age (P -/+ 0.038), uric acid (P < 0.001), body mass index (P -/+ 0.01), plasminogen (P -/+ 0.013), and fibrinogen (P -/+ 0.002) in bivariate regression analyses, whereas HDL-cholesterol (P -/+ 0.005) was shown to be negatively correlated. However, investigating confounding effects in stepwise multivariate regression analysis, body mass index (P -/+ 0.009), uric acid (P -/+ 0.026) and age (P -/+ 0.037) turned out to be significantly associated with plasma levels of circulating TNF-alpha (adjusted R(2) -/+ 0.117; SE: 0.688).
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(Journal Article): Prediction and pathogenesis in type 1 diabetes
Ziegler AG, Nepom GT (Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Kölner Platz 1, 80804 München, Germany,
anziegler@lrz.uni-muenchen.de
)
IN:
Immunity
2010; 32(4):468-478
Impact Factor(s) of Immunity: 1.545 (2004), 16.016 (2003), 17.468 (2002), 18.866 (2001)
ABSTRACT: A combination of genetic and immunological features is useful for prediction of autoimmune diabetes. Patterns of immune response correspond to the progression from a preclinical phase of disease to end-stage islet damage, with biomarkers indicating transition from susceptibility to active autoimmunity, and to a final loss of immune regulation. Here, we review the markers that provide evidence for immunological checkpoint failure and that also provide tools for assessment of individualized disease risk. When viewed in the context of genetic variation that influences immune response thresholds, progression from susceptibility to overt disease displays predictable modalities of clinical presentation resulting from a sequential series of failed homeostatic checkpoints for selection and activation of immunity.
TYPE OF PUBLICATION: Review
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