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

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.