title: Influence of the confounding factors age and sex on microRNA profiles from peripheral blood.
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.
authors.affiliation: 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;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Department of Human Genetics, Saarland University, Homburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Human Genetics, Saarland University, Homburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Leidinger
authors.affiliation: Siemens Healthcare, Erlangen, Germany;
authors.forename: Cord
authors.initials: C
authors.lastname: Stähler
authors.affiliation: Clinical Bioinformatics, Saarland University, Saarbrucken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Großmann
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany;
authors.forename: Britta
authors.initials: B
authors.lastname: Vogel
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany;
authors.forename: Karen
authors.initials: K
authors.lastname: Frese
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany;
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giannitsis
authors.affiliation: 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;
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Human Genetics, Saarland University, Homburg, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Meese
authors.affiliation: Clinical Bioinformatics, Saarland University, Saarbrucken, Germany. andreas.keller@ccb.uni-saarland.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D046228:Microarray Analysis; D008875:Middle Aged; D012015:Reference Standards; D012737:Sex Factors; D059467:Transcriptome
chemical_list: D035683:MicroRNAs