Benjamin Meder1, Christina Backes2, Jan Haas3, Petra Leidinger2, Cord Stähler4, Thomas Großmann5, Britta Vogel6, Karen Frese6, Evangelos Giannitsis6, Hugo A Katus1, Eckart Meese2, Andreas Keller7. 1. Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany; Klaus Tschira Institute for Integrative Computational Cardiology, Heidelberg, Germany; 2. Department of Human Genetics, Saarland University, Homburg, Germany. 3. Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany; 4. Siemens Healthcare, Erlangen, Germany; 5. Clinical Bioinformatics, Saarland University, Saarbrucken, Germany. 6. Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany; 7. Clinical Bioinformatics, Saarland University, Saarbrucken, Germany. andreas.keller@ccb.uni-saarland.de.
Abstract
BACKGROUND: MicroRNAs (miRNAs) measured from blood samples are promising minimally invasive biomarker candidates that have been extensively studied in several case-control studies. However, the influence of age and sex as confounding variables remains largely unknown. METHODS: We systematically explored the impact of age and sex on miRNAs in a cohort of 109 physiologically unaffected individuals whose blood was characterized by microarray technology (stage 1). We also investigated an independent cohort from a different institution consisting of 58 physiologically unaffected individuals having a similar mean age but with a smaller age distribution. These samples were measured by use of high-throughput sequencing (stage 2). RESULTS: We detected 318 miRNAs that were significantly correlated with age in stage 1 and, after adjustment for multiple testing of 35 miRNAs, remained statistically significant. Regarding sex, 144 miRNAs showed significant dysregulation. Here, no miRNA remained significant after adjustment for multiple testing. In the high-throughput datasets of stage 2, we generally observed a smaller number of significant associations, mainly as an effect of the smaller cohort size and age distribution. Nevertheless, we found 7 miRNAs that were correlated with age, of which 5 were concordant with stage 1. CONCLUSIONS: The age distribution of individuals recruited for case-control studies needs to be carefully considered, whereas sex may be less confounding. To support the translation of miRNAs into clinical application, we offer a web-based application (http://www.ccb.uni-saarland.de/mirnacon) to test individual miRNAs or miRNA signatures for their likelihood of being influenced.
BACKGROUND: MicroRNAs (miRNAs) measured from blood samples are promising minimally invasive biomarker candidates that have been extensively studied in several case-control studies. However, the influence of age and sex as confounding variables remains largely unknown. METHODS: We systematically explored the impact of age and sex on miRNAs in a cohort of 109 physiologically unaffected individuals whose blood was characterized by microarray technology (stage 1). We also investigated an independent cohort from a different institution consisting of 58 physiologically unaffected individuals having a similar mean age but with a smaller age distribution. These samples were measured by use of high-throughput sequencing (stage 2). RESULTS: We detected 318 miRNAs that were significantly correlated with age in stage 1 and, after adjustment for multiple testing of 35 miRNAs, remained statistically significant. Regarding sex, 144 miRNAs showed significant dysregulation. Here, no miRNA remained significant after adjustment for multiple testing. In the high-throughput datasets of stage 2, we generally observed a smaller number of significant associations, mainly as an effect of the smaller cohort size and age distribution. Nevertheless, we found 7 miRNAs that were correlated with age, of which 5 were concordant with stage 1. CONCLUSIONS: The age distribution of individuals recruited for case-control studies needs to be carefully considered, whereas sex may be less confounding. To support the translation of miRNAs into clinical application, we offer a web-based application (http://www.ccb.uni-saarland.de/mirnacon) to test individual miRNAs or miRNA signatures for their likelihood of being influenced.
Authors: Tobias Fehlmann; Christina Backes; Marcello Pirritano; Thomas Laufer; Valentina Galata; Fabian Kern; Mustafa Kahraman; Gilles Gasparoni; Nicole Ludwig; Hans-Peter Lenhof; Henrike A Gregersen; Richard Francke; Eckart Meese; Martin Simon; Andreas Keller Journal: Nucleic Acids Res Date: 2019-05-21 Impact factor: 16.971
Authors: Klaasjan G Ouwens; Rick Jansen; Michel G Nivard; Jenny van Dongen; Maia J Frieser; Jouke-Jan Hottenga; Wibowo Arindrarto; Annique Claringbould; Maarten van Iterson; Hailiang Mei; Lude Franke; Bastiaan T Heijmans; Peter A C 't Hoen; Joyce van Meurs; Andrew I Brooks; Brenda W J H Penninx; Dorret I Boomsma Journal: Eur J Hum Genet Date: 2019-09-26 Impact factor: 4.246
Authors: Nicole Ludwig; Anne Hecksteden; Mustafa Kahraman; Tobias Fehlmann; Thomas Laufer; Fabian Kern; Tim Meyer; Eckart Meese; Andreas Keller; Christina Backes Journal: RNA Biol Date: 2019-05-10 Impact factor: 4.652
Authors: Nicole Ludwig; Petra Leidinger; Kurt Becker; Christina Backes; Tobias Fehlmann; Christian Pallasch; Steffi Rheinheimer; Benjamin Meder; Cord Stähler; Eckart Meese; Andreas Keller Journal: Nucleic Acids Res Date: 2016-02-25 Impact factor: 16.971
Authors: Wolfgang Poller; Stefanie Dimmeler; Stephane Heymans; Tanja Zeller; Jan Haas; Mahir Karakas; David-Manuel Leistner; Philipp Jakob; Shinichi Nakagawa; Stefan Blankenberg; Stefan Engelhardt; Thomas Thum; Christian Weber; Benjamin Meder; Roger Hajjar; Ulf Landmesser Journal: Eur Heart J Date: 2018-08-01 Impact factor: 29.983