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Open Access Research article

Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis

Santhi K Ganesh1, Jungnam Joo2, Kimberly Skelding3, Laxmi Mehta4, Gang Zheng2, Kathleen O'Neill1, Eric M Billings1, Anna Helgadottir5, Karl Andersen67, Gudmundur Thorgeirsson67, Thorarinn Gudnason6, Nancy L Geller2, Robert D Simari8, David R Holmes8, William W O'Neill9 and Elizabeth G Nabel1*

Author Affiliations

1 National Heart, Lung, and Blood Institute (NHLBI), Division of Intramural Research, Bethesda, Maryland, USA

2 Office of Biostatistics Research, National Heart Lung and Blood Institute, National Institutes of Health, USA

3 Geisinger Clinic, Danville, Pennsylvania, USA

4 Division of Cardiovascular Medicine, Ohio State University Medical Center, Columbus, Ohio, USA

5 Department of Cardiovascular Medicine, Wellcome Trust Centre of Human Genetics, Oxford, UK

6 Cardiovascular Research Center, Landspitali University Hospital, Reykjavik, Iceland

7 University of Iceland, Reykjavik, Iceland

8 Divsion of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA

9 Division of Cardiology, Department of Internal Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA

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BMC Medical Genomics 2011, 4:20  doi:10.1186/1755-8794-4-20

Published: 28 February 2011

Abstract

Background

The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not.

Methods and Results

We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes.

Conclusions

In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.