Original Paper

Inflammatory Gene Haplotype-Interaction Networks Involved in Coronary Collateral Formation
Jian Zhang^a, Jakub J. Regieli^{b, e}, Maria Schipper^c, Mark M. Entius^b, Faming Liang^f, Jeroen Koerselman^e, Hendrik J.T. Ruven^d, Yolanda van der Graaf^e, Diederick E. Grobbee^e, Pieter A. Doevendans<sup>b

a</sup>Institute of Mathematics, Statistics and Actuarial Science, University of Kent, Canterbury, Kent, UK;
^bDepartment of Cardiology, UMC Utrecht,
^cDepartment of Biostatistics, Utrecht University, Utrecht,
^dDepartment of Clinical Chemistry St. Antonius Hospital, Nieuwegein, and
^eJulius Centre for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands;
^fDepartment of Statistics, Texas A&M University, College Station, Tex., USA

Address of Corresponding Author

Hum Hered 2008;66:252-264 (DOI: 10.1159/000143407)

  Key Words

• Atherosclerosis
• Genetics
• Inflammation
• Coronary heart disease
• Collateral circulation
• Risk factors

  Abstract

Objectives: Formation of collateral circulation is an endogenous response to atherosclerosis, and is a natural escape mechanism by re-routing blood. Inflammatory response- related genes underlie the formation of coronary collaterals. We explored the genetic basis of collateral formation in man postulating interaction networks between functional Single Nucleotide Polymorphisms (SNPs) in these inflammatory gene candidates. Methods: The contribution of 41 genes as well as the interactions among them was examined in a cohort of 226 coronary artery disease patients, genotyped for 54 candidate SNPs. Patients were classified to the extent of collateral circulation. Stepwise logistic regression analysis and a haplotype entropy procedure were applied to search for haplotype interactions among all 54 polymorphisms. Multiple testing was addressed by using the false discovery rate (FDR) method. Results: The population comprised 84 patients with and 142 without visible collaterals. Among the 41 genes, 16 pairs of SNPs were implicated in the development of collaterals with the FDR of 0.19. Nine SNPs were found to potentially have main effects on collateral formation. Two sets of coupling haplotypes that predispose to collateral formation were suggested. Conclusions: These findings suggest that collateral formation may arise from the interactions between several SNPs in inflammatory response related genes, which may represent targets in future studies of collateral formation. This may enhance developing strategies for risk stratification and therapeutic stimulation of arteriogenesis.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Prof. P.A. Doevendans
Department of Cardiology, University Medical Centre Utrecht
Heidelberglaan 100
NL-3584 CX, Utrecht (The Netherlands)
Tel. +31 30 250 6176, Fax +31 30 250 5423, E-Mail p.doevendans@umcutrecht.nl

  Article Information

J. Zhang and J.J. Regieli contributed equally to this work.

Received: July 2, 2007
Accepted after revision: November 26, 2007
Published online: July 9, 2008
Number of Print Pages : 13
Number of Figures : 2, Number of Tables : 9, Number of References : 31