title: Urinary chromium is associated with changes in leukocyte miRNA expression in obese subjects.
abstract: Epidemiological studies suggest a link between chromium (Cr) status and cardiovascular disease. Increased urinary excretion of Cr was reported in subjects with diabetes compared with non-diabetic controls and those with non-diabetic insulin resistance. Epigenetic alterations have been linked to the presence of Cr, and microRNA (miRNA) expression has been implicated in the pathogenesis of metabolic diseases and cardiovascular diseases (CVDs). We investigated the association between Cr excretion and miRNA expression in leukocytes from obese subjects. We also examined the relationship between altered miRNA expression and selected clinical parameters to further investigate mechanisms linking Cr to metabolic diseases and CVDs.
  
  
  
  We analyzed urinary Cr in 90 Italian subjects using inductively coupled plasma-mass spectrometry. Peripheral blood miRNA levels were screened with TaqMan Low-Density Array Human MicroRNA A. Cr level-associated expression of miRNAs was detected with multivariate regression analyses, and the top 10 candidate miRNAs were selected for validation. We also used multivariate regression analyses to assess possible associations between validated miRNAs and glycated hemoglobin (A1c) and blood pressure (BP). The validated miRNAs were further investigated by functional analysis with Ingenuity Pathway Analysis software.
  
  
  
  Urinary Cr levels (mean: 0.35 μg/l; s.d.=0.24) ranged from 0.05 to 1.27 μg/l. In the screening phase, 43 miRNAs were negatively associated with Cr. Of the top 10 miRNAs selected for validation, nine (miR-451, miR-301, miR-15b, miR-21, miR-26a, miR-362-3p, miR-182, miR-183 and miR-486-3p) were downregulated in association with Cr (P-false discovery rate (FDR)<0.10). miR-451 expression was associated with A1c (β=-0.06; P=0.0416), whereas miR-486-3p expression was associated both with diastolic (β=2.1; P=0.004) and systolic BP (β=3.3; P=0.003).
  
  
  
  These results indicate that miR-451 and miR-486-3p are involved in the link between Cr levels and metabolic diseases and CVDs.
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Dioni
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Sucato
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Motta
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iodice
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Angelici
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Favero
authors.affiliation: Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Cavalleri
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Preventive Medicine, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Vigna
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Albetti
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Preventive Medicine, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Fustinoni
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Preventive Medicine, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bertazzi
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Preventive Medicine, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pesatori
authors.affiliation: EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Preventive Medicine, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bollati
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics; D016022:Case-Control Studies; D002857:Chromium / Q000652:urine*; D015536:Down-Regulation; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000652:urine*; D012044:Regression Analysis; D055815:Young Adult
chemical_list: D002857:Chromium; D006442:Glycated Hemoglobin; D035683:MicroRNAs; C517652:hemoglobin A1c protein, human