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

Congrui Feng, Yunyun Yang, Shujun Yang, Xin Tu, Yibo Wang, Yiqing Song, Rutai Hui, Weili Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere846
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue number8
DOIs
StatePublished - Jan 1 2019

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Stroke
Vitamin K Epoxide Reductases
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor A
5-Lipoxygenase-Activating Proteins
Multifactor Dimensionality Reduction
Logistic Models
Apoprotein(a)
Methylenetetrahydrofolate Reductase (NADPH2)
Carotid Intima-Media Thickness
Carotid Arteries
Case-Control Studies
Chromosomes
Alleles
Hypertension
Recurrence
Mortality
Genes

Keywords

  • case-control study
  • genetics
  • gene–gene interaction
  • risk factors
  • stroke

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Effect of gene–gene and gene–environment interaction on the risk of first-ever stroke and poststroke death. / Feng, Congrui; Yang, Yunyun; Yang, Shujun; Tu, Xin; Wang, Yibo; Song, Yiqing; Hui, Rutai; Zhang, Weili.

In: Molecular Genetics and Genomic Medicine, Vol. 7, No. 8, e846, 01.01.2019.

Research output: Contribution to journalArticle

Feng, Congrui ; Yang, Yunyun ; Yang, Shujun ; Tu, Xin ; Wang, Yibo ; Song, Yiqing ; Hui, Rutai ; Zhang, Weili. / Effect of gene–gene and gene–environment interaction on the risk of first-ever stroke and poststroke death. In: Molecular Genetics and Genomic Medicine. 2019 ; Vol. 7, No. 8.
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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.",
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T1 - Effect of gene–gene and gene–environment interaction on the risk of first-ever stroke and poststroke death

AU - Feng, Congrui

AU - Yang, Yunyun

AU - Yang, Shujun

AU - Tu, Xin

AU - Wang, Yibo

AU - Song, Yiqing

AU - Hui, Rutai

AU - Zhang, Weili

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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