Plasma concentrations of afamin are associated with the metabolic syndrome and related diseases

Transcription

1 Plasma concentrations of afamin are associated with the metabolic syndrome and related diseases Hans Dieplinger Division of Genetic Epidemiology Medical University of Innsbruck, Austria 6 th Munich Biomarker Conference 2016 Afamin Glycoprotein, 87 kda Albumin gene family In vitro vitamin E binding property Expressed primarily in liver, secreted into circulating blood 1

2 Putative (patho)physiological functions of afamin Male and female fertility Neuroprotective function Marker for ovarian cancer Carrier/solubilizer of Wnt proteins Preliminary findings in transgenic mice (overexpressing human afamin) Hyperlipemic, hyperglycemic and obese phenotype Possibly relevant for epidemic disorders such as the metabolic syndrome and related diseases Preliminary findings in transgenic mice 2

3 Metabolic syndrome - a constellation of metabolic abnormalities (ATP III criteria - AHA/NHLBI statement) Elevated glucose concentration Elevated waist circumference Reduced HDL-C Elevated triglycerides Hypertension Any 3 of 5 define diagnosis of metabolic syndrome Grundy et al., Circulation 2005;112: Three independent populations (n=5.385) 2 population-based studies (n=3.886) Bruneck (n=826): Gender- and age-stratified random sample of all inhabitants of Bruneck, Italy; follow-up examinations performed in 1995, 2000, 2005 and 2010 KORA F4 (n=3.060): cohort representative of the general population in Augsburg, Germany and two surrounding counties, recruited healthy working population (n=1.499) SAPHIR: conducted in Salzburg, Austria, in the years involving healthy unrelated subjects; follow up investigation

4 Afamin and components of the metabolic syndrome Study HDL cholesterol Parameter Waist circumference Triglycerides Glucose SBP DBP Bruneck SAPHIR KORA F4 SBP: systolic blood pressure; DBP: diastolic blood pressure + parameter increases per tertile group of afamin - parameter decreases per tertile group of afamin Prevalent metabolic syndrome components Afamin and prevalence of metabolic syndrome 4

5 Afamin and incidence of metabolic syndrome Diagnostic ability of afamin predicting incidence of metabolic syndrome (results from SAPHIR study) AUC (unadjusted)= Model including age and sex: C-statistic: Model including age, sex and Afamin: C-statistic: Does Afamin add significantly to the model? p=6.575e-34 5

6 A meta-analysis of the association of afamin with type 2 diabetes mellitus (T2DM) in more than 20,000 individuals 6 population-based studies (Bruneck, n=826; KORA F3, n=3.136; KORA F4, n=3.050; CoLaus, n=4.773; YFS, n=2.270; NHLBI Family Heart Study, n=1.877) 1 prospective study with data collected from general medical practices (NPHS-II, n=2.674) 1 healthy working population (SAPHIR, n=1.488) Kollerits et al., unpublished Global projections for the Diabetes Epidemic: NA EUR 23.0 M 36.2 M 57.0% 48.4 M 58.6 M 21% EMME 19.2 M 39.4 M 105% SEA WP 43.0 M 75.8 M 79% World 2003 = 194 M 2025 = 333 M 72% SACA 14.2 M 26.2 M 85% AFR 7.1M 15.0 M 111% 39.3 M 81.6 M 108% M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific 6

7 Afamin and prevalent T2DM Each increase of afamin by 10 mg/l was associated with a higher probability for prevalent T2DM (n=1,398): OR=1.19 (95%CI ), p=5.96x10-8 (adjustment for age, sex, BMI, HDL cholesterol, triglycerides, hypertension). Kollerits et al., unpublished Afamin and incident T2DM Increasing afamin concentrations (increment 10 mg/l) were a significant predictor for incident T2DM (n=585): OR=1.30 (95%CI ), p=3.53x10-19 Kollerits et al., unpublished 7

8 Afamin is strongly associated with NAFLD Young Finns Study (YFS, n=2042) Case/Control Study Innsbruck/Saphir (n=146, 45, 292) Oikonen et al., unpublished Afamin in patients with metabolic-syndrome like phenotypes Pregnancy complications first trimester screening for afamin to predict Gestational Diabetes Mellitus (GDM) and preeclampsia Mann-Whitney-U test p<0.001 Mann-Whitney-U test p=0.001 (n=209) (n=209) (n=30) (n=30) Tramontana et al., unpublished 8

9 Summary Transgenic mice show a hyperlipemic, hyperglycemic and obese phenotype Afamin concentration at baseline is highly significantly related to: All single metabolic syndrome components at baseline and follow-up Afamin is predictive for the development of metabolic syndrome and all its components Afamin is associated with prevalent and incident diabetes, liver steatosis and pregnancy complications possibly causal role of afamin for metabolic syndrome and related diseases Genetic Epidemiology, Medical University of Innsbruck, Austria Barbara Kollerits, Claudia Lamina, Linda Fineder, Doreen Dähnhardt, Andreas Melmer, Georg Wietzorrek, Ramona Berberich, Florian Kronenberg University of Göttingen, Germany Ibrahim M. Adham, Maria E. Altmann, Wolfgang Engel Department of Neurology, Medical University of Innsbruck, Austria (Bruneck Study) Peter Santer, Stefan Kiechl, Johann Willeit First Department of Internal Medicine, Paracelsus Private Medical University Salzburg, Austria (SAPHIR Study) Ludmilla Kedenko, Bernhard Paulweber Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria Armin Finkenstedt, Heinz Zoller KORA F4 Study Cornelia Huth, Barbara Thorand, Wolfgang Rathmann, Christa Meisinger, Annette Peters CoLaus Study Pedro Marques-Vidal, Peter Vollenweider German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany Michael Roden NPHSII Steve Humphries et al. YFS Mervi Oikonen et al. Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, USA Steven Hunt Hospital SMZ-Ost, Vienna Allessandra Tramontana, Erich Hafner Acknowledgments 9