Pathway analysis using genome-wide association study data for coronary restenosis--a potential role for the PARVB gene.
BACKGROUND
Coronary restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. The causative mechanisms of restenosis have not yet been fully identified. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition.


METHODS
The GENetic DEterminants of Restenosis (GENDER) databank contains genotypic data of 556,099SNPs of 295 cases with restenosis and 571 matched controls. Fifty-four pathways, related to known restenosis-related processes, were selected. Gene-set analysis was performed using PLINK, GRASS and ALIGATOR software. Pathways with a p<0.01 were fine-mapped and significantly associated SNPs were analyzed in an independent replication cohort.


RESULTS
Six pathways (cell-extracellular matrix (ECM) interactions pathway, IL2 signaling pathway, IL6 signaling pathway, platelet derived growth factor pathway, vitamin D receptor pathway and the mitochondria pathway) were significantly associated in one or two of the software packages. Two SNPs in the cell-ECM interactions pathway were replicated in an independent restenosis cohort. No replication was obtained for the other pathways.


CONCLUSIONS
With these results we demonstrate a potential role of the cell-ECM interactions pathway in the development of coronary restenosis. These findings contribute to the increasing knowledge of the genetic etiology of restenosis formation and could serve as a hypothesis-generating effort for further functional studies.
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Jeffrey J W
JJ
Verschuren
Stella
S
Trompet
M Lourdes
ML
Sampietro
Bastiaan T
BT
Heijmans
Werner
W
Koch
Adnan
A
Kastrati
Jeanine J
JJ
Houwing-Duistermaat
P Eline
PE
Slagboom
Paul H A
PH
Quax
J Wouter
JW
Jukema
D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D016022:Case-Control Studies; D023903:Coronary Restenosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D015398:Signal Transduction; D012984:Software
D016207:Cytokines; C486591:PARVB protein, human; D000185:Actinin