Effect of gene–gene and gene–environment interaction on the risk of first-ever stroke and poststroke death

Abstract

Background: Multiple genetic and environmental factors contribute to the individual-level heterogeneity in stroke. This study aimed to assess how the genetic interactions confer risk of stroke. Methods: In a Chinese case-control study including 1,405 strokes and 1,263 controls who were followed up (range, 0.1–6.0 years), eight genes, including apolipoprotein(a) (APOA1), methylenetetrahydrofolate reductase (MTHFR), vitamin K epoxide reductase complex subunit 1 (VKORC1), arachidonate 5-lipoxygenase-activating protein (ALOX5AP), NOTCH3, chromosome 9p21.3(Chr.9p21.3), vascular endothelial growth factor (VEGFA), and kinase insert domain-containing receptor (KDR), were analyzed for interactions by the generalized multifactor dimensionality reduction method and validated by the multivariate logistic regression models. The genetic associations with carotid artery intima-media thickness (IMT) were examined. Results: The interaction of VKORC1 and Chr.9p21.3 was identified for stroke and its worse prognosis, and subjects having the VKORC1 rs2359612C and Chr.9p21.3 rs10757274G alleles had higher risks for stroke (OR = 1.83, 95% CI = 1.32–2.52) as well as for stroke recurrence (HR = 1.84, 95% CI = 1.24–2.73), cardiovascular events (HR = 1.65, 95% CI = 1.15–2.38), and cardiovascular mortality (HR = 2.16, 95% CI = 1.24–3.79). Supporting, they were associated with higher IMT. Hypertension or physical inactivity increased the risk effect. The interaction of VEGFA rs833061C and KDR rs2305948T was identified for hemorrhagic stroke. Conclusions: Our findings identified two novel genetic interactions of VKORC1 and Chr.9p21.3 and of VEGFA and KDR for risk of stroke and subtypes as well as future stroke prognosis.