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

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

Author information

1
Epidemiology and Public Health, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
2
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.
3
Institute of Biomedical and Clinical Sciences, Medical School, University of Exeter, RILD, Exeter EX2 5DW, UK.
4
Institute for Health Services Research, University of Exeter Medical School, Exeter EX1 2LU, UK.
5
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.
6
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.
7
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
8
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.
9
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.
10
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.
11
Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA. Electronic address: ferruccilu@grc.nia.nih.gov.

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

PMID:
26087330
PMCID:
PMC4600657
DOI:
10.1016/j.exger.2015.05.012
[Indexed for MEDLINE]
Free PMC Article

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