title: Gene expression markers of age-related inflammation in two human cohorts.
abstract: BACKGROUND
  Chronically elevated circulating inflammatory markers are common in older persons but mechanisms are unclear. Many blood transcripts (>800 genes) are associated with interleukin-6 protein levels (IL6) independent of age. We aimed to identify gene transcripts statistically mediating, as drivers or responders, the increasing levels of IL6 protein in blood at older ages.
  
  
  METHODS
  Blood derived in-vivo RNA from the Framingham Heart Study (FHS, n=2422, ages 40-92 yrs) and InCHIANTI study (n=694, ages 30-104 yrs), with Affymetrix and Illumina expression arrays respectively (>17,000 genes tested), were tested for statistical mediation of the age-IL6 association using resampling techniques, adjusted for confounders and multiple testing.
  
  
  RESULTS
  In FHS, IL6 expression was not associated with IL6 protein levels in blood. 102 genes (0.6% of 17,324 expressed) statistically mediated the age-IL6 association of which 25 replicated in InCHIANTI (including 5 of the 10 largest effect genes). The largest effect gene (SLC4A10, coding for NCBE, a sodium bicarbonate transporter) mediated 19% (adjusted CI 8.9 to 34.1%) and replicated by PCR in InCHIANTI (n=194, 35.6% mediated, p=0.01). Other replicated mediators included PRF1 (perforin, a cytolytic protein in cytotoxic T lymphocytes and NK cells) and IL1B (Interleukin 1 beta): few other cytokines were significant mediators.
  
  
  CONCLUSIONS
  This transcriptome-wide study on human blood identified a small distinct set of genes that statistically mediate the age-IL6 association. Findings are robust across two cohorts and different expression technologies. Raised IL6 levels may not derive from circulating white cells in age related inflammation.
authors.affiliation: Epidemiology and Public Health, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Pilling
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Epidemiology and Public Health, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.affiliation: Institute of Biomedical and Clinical Sciences, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Institute for Health Services Research, University of Exeter Medical School, Exeter EX1 2LU, UK.
authors.forename: William
authors.initials: W
authors.lastname: Henley
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Institute of Biomedical and Clinical Sciences, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA.
authors.forename: Sai-Xia
authors.initials: SX
authors.lastname: Ying
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; The Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institute of Health, Bethesda, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Munson
authors.affiliation: National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA. Electronic address: ferruccilu@grc.nia.nih.gov.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005819:Genetic Markers / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6
keywords: Aging; Blood; Epidemiology; Human; Inflammation; Transcriptome