Genetically reduced soluble epoxide hydrolase activity and risk of stroke and other cardiovascular disease.
OBJECTIVE
The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the cerebral microvasculature. These substances are metabolized by the enzyme-soluble epoxide hydrolase encoded by the EPHX2 gene. We tested whether genetically reduced soluble epoxide hydrolase activity is associated with risk of ischemic stroke, myocardial infarction, and ischemic heart disease.


METHODS
We genotyped participants from the Copenhagen City Heart Study (n=10 352), the Copenhagen General Population Study (n=26 042), the Copenhagen Carotid Stroke Study (n=398 cases+796 control subjects), and the Copenhagen Ischemic Heart Disease Study (n=4901 cases+9798 control subjects) for the R103C, R287Q, and Arg(402-403ins) variants in the EPHX2 gene and recorded hospital admissions due to ischemic stroke, myocardial infarction, and ischemic heart disease.


RESULTS
The hazard/odds ratio for ischemic stroke did not differ from 1.0 for any of the EPHX2 genotypes or genotype combinations in the Copenhagen City Heart Study (P for trend=0.15 to 0.76), in the Copenhagen General Population Study (P for trend=0.75 to 0.95), and the Copenhagen Carotid Stroke Study (P for trend=0.08 to 1.00). Similar results were obtained for myocardial infarction and ischemic heart disease in the 3 studies.


CONCLUSIONS
Our results show with significant power that genetically reduced soluble epoxide hydrolase activity is not a major risk factor for ischemic stroke, myocardial infarction, or ischemic heart disease in the Danish population. This suggests that the relationship between the EPHX2 gene and risk of ischemic stroke and other cardiovascular disease does not exist or its effect size is likely to be quite small.
Lee
Julie
J
Department of Clinical Biochemistry K54M1, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Dahl
Morten
M
Grande
Peer
P
Tybjaerg-Hansen
Anne
A
Nordestgaard
Børge G
BG
D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004789:Enzyme Activation / Q000235:genetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human