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Missense Variants in Hypoxia-Induced VEGFA/VEGFR2 Signaling Predict the Outcome of Large Artery Atherosclerotic Stroke

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Abstract

Collateral density variations are a major determinant of stroke outcome. Here, we explored the association of missense variants in hypoxia-induced VEGFA/VEGFR2 signaling and stroke outcome. We recruited 683 large artery atherosclerotic (LAA) stroke patients as the training set from Nanjing Stroke Registry Program between August 2013 and January 2016. To validate the findings from the training set, we recruited an additional 333 LAA stroke patients between February 2016 and January 2017 as the validation set. Genotyping of target SNPs (rs11549465 [HIF-1α], rs11549467 [HIF-1α], rs1870377 [VEGFR2], and rs2305948 [VEGFR2]) was conducted using a SNPscan method. Unfavorable outcome was defined as a modified Rankin Scale (mRS) score > 2 at three months after index event. In the training set, the AA genotype of rs1870377 led to a decreased risk of unfavorable outcomes in the recessive model (AA vs. TA + TT, OR 0.60, 95% CI 0.38–0.95, P = 0.031). This was confirmed in the validation set (OR 0.43, 95% CI 0.21–0.86, P = 0.017) and the combined set (OR 0.54, 95% CI 0.36–0.79, P = 0.002). We also found that A allele was a protective factor for stroke outcome in both validation set and combined set (OR 0.70, 95% CI 0.49–0.99, P = 0.044 and OR 0.77, 95% CI 0.63–0.94, P = 0.012, respectively). In silico analysis indicated that the rs1870377 variant led to structural alterations in VEGFR2 that may influence its activity. Our findings demonstrate that the rs1870377 in the hypoxia-induced VEGFA/VEGFR2 axis predicts the 3-month outcome of patients with LAA stroke.

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Abbreviations

HIF-1α:

Hypoxia inducible factor-1α;

VEGFA:

Vascular endothelial growth factor A;

VEGFR2:

Vascular endothelial growth factor receptor 2

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Acknowledgements

We also thank Ying Lin and Zhaojun Wang (Jinling Hospital, Medical School of Nanjing University) for their supports in collecting baseline data.

Funding

This study was funded by National Natural Science Foundation of China (81530038, 81571148 and 81771285), China Postdoctoral Science Foundation (2016M592954), and Natural Science Foundation of Wannan Medical college (WK2019F08).

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Author notes

  1. Zibao Li and Mengmeng Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Jinling Hospital, Nanjing Medical University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China

    Zibao Li, Jinyu Gu, Zhizhong Zhang & Xinfeng Liu

  2. Department of Neurology, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China

    Zibao Li & Li Zhao

  3. Department of Neurology, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, China

    Mengmeng Wang

  4. Department of Neurology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, China

    Yongtao Guo

  5. Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China

    Zhizhong Zhang & Xinfeng Liu

Authors
  1. Zibao Li
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Contributions

XL and ZZ performed study design and edited the manuscript. ZL and MW analyzed the data and prepared the manuscript. JG, LZ, and YG collected the clinical data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhizhong Zhang or Xinfeng Liu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Li, Z., Wang, M., Gu, J. et al. Missense Variants in Hypoxia-Induced VEGFA/VEGFR2 Signaling Predict the Outcome of Large Artery Atherosclerotic Stroke. Cell Mol Neurobiol 41, 1217–1225 (2021). https://doi.org/10.1007/s10571-020-00890-7

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