Gene expression markers of age-related inflammation in two human cohorts

Exp Gerontol. 2015 Oct;70:37-45. doi: 10.1016/j.exger.2015.05.012. Epub 2015 Jun 16.

Abstract

Introduction: 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.

Keywords: Aging; Blood; Epidemiology; Human; Inflammation; Transcriptome.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Aging / immunology
  • Biomarkers / blood
  • Cohort Studies
  • Female
  • Gene Expression Profiling / methods
  • Genetic Markers / physiology
  • Humans
  • Inflammation / genetics*
  • Inflammation / immunology
  • Inflammation Mediators / blood*
  • Interleukin-6 / blood
  • Interleukin-6 / genetics
  • Male
  • Middle Aged

Substances

  • Biomarkers
  • Genetic Markers
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6