Inflammatory Gene Haplotype-Interaction Networks Involved in Coronary Collateral Formation

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Zhang, Jian ; Regieli, Jakub J ; Schipper, Maria ; Entius, Mark M. ; Liang, Faming ; Koerselman, Jeroen ; Ruven, Hendrik J.T. ; van der Graaf, Yolanda ; Grobbee, Diederick E ; Doevendans, Pieter A. (2008)

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