Inflammatory Gene Haplotype-Interaction Networks Involved in Coronary Collateral Formation

Objectives: Formation of collateral circulation is an endogenous

response to atherosclerosis, and is a natural escape

mechanism by re-routing blood. Inflammatory responserelated

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.