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Open Access Highly Accessed Research article

Identification of candidate genes linking systemic inflammation to atherosclerosis; results of a human in vivo LPS infusion study

Suthesh Sivapalaratnam1*, Rosienne Farrugia2, Max Nieuwdorp1, Cordelia F Langford3, Rachel T van Beem4, Stephanie Maiwald1, Jaap Jan Zwaginga4, Arief Gusnanto5, Nicholas A Watkins26, Mieke D Trip1 and Willem H Ouwehand236

Author Affiliations

1 Department of Vascular Medicine, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands

2 Department of Hematology, University of Cambridge, Long Road, CB2 0PT, Cambridge, UK

3 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, Cambridge, UK

4 Department of Experimental Immunohematology, Sanquin Research, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands

5 Department of Statistics, University of Leeds, Woodhouse lane, LS2 9JT, Leeds, UK

6 National Health Service Blood and Transplant, Cambridge, Long Road, CB2 0PT, UK

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BMC Medical Genomics 2011, 4:64  doi:10.1186/1755-8794-4-64

Published: 10 August 2011

Abstract

Background

It is widely accepted that atherosclerosis and inflammation are intimately linked. Monocytes play a key role in both of these processes and we hypothesized that activation of inflammatory pathways in monocytes would lead to, among others, proatherogenic changes in the monocyte transcriptome. Such differentially expressed genes in circulating monocytes would be strong candidates for further investigation in disease association studies.

Methods

Endotoxin, lipopolysaccharide (LPS), or saline control was infused in healthy volunteers. Monocyte RNA was isolated, processed and hybridized to Hver 2.1.1 spotted cDNA microarrays. Differential expression of key genes was confirmed by RT-PCR and results were compared to in vitro data obtained by our group to identify candidate genes.

Results

All subjects who received LPS experienced the anticipated clinical response indicating successful stimulation. One hour after LPS infusion, 11 genes were identified as being differentially expressed; 1 down regulated and 10 up regulated. Four hours after LPS infusion, 28 genes were identified as being differentially expressed; 3 being down regulated and 25 up regulated. No genes were significantly differentially expressed following saline infusion. Comparison with results obtained in in vitro experiments lead to the identification of 6 strong candidate genes (BATF, BID, C3aR1, IL1RN, SEC61B and SLC43A3)

Conclusion

In vivo endotoxin exposure of healthy individuals resulted in the identification of several candidate genes through which systemic inflammation links to atherosclerosis.

Keywords:
Human; Monocytes; LPS infusion; Transcriptome; In Vivo