Inflammatory gene haplotype-interaction networks involved in coronary collateral formation.
OBJECTIVE
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.
Zhang
Jian
J
Institute of Mathematics, Statistics and Actuarial Science, University of Kent, Canterbury, Kent, UK.
Regieli
Jakub J
JJ
Schipper
Maria
M
Entius
Mark M
MM
Liang
Faming
F
Koerselman
Jeroen
J
Ruven
Hendrik J T
HJ
van der Graaf
Yolanda
Y
Grobbee
Diederick E
DE
Doevendans
Pieter A
PA
D000368:Aged; D003097:Collateral Circulation / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors