Cardiovascular risk associated with interactions among polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems.
BACKGROUND
Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study.


RESULTS
Data from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015).


CONCLUSIONS
This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed.
Bentley
John P
JP
Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, Mississippi, United States of America.
Asselbergs
Folkert W
FW
Coffey
Christopher S
CS
Hebert
Patricia R
PR
Moore
Jason H
JH
Hillege
Hans L
HL
van Gilst
Wiek H
WH
D000328:Adult; D000368:Aged; D001920:Bradykinin / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics*; D044465:White People / Q000235:genetics
D010959:Tissue Plasminogen Activator; D001920:Bradykinin