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Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation
  1. Junyu Liu1,2,
  2. Yifeng Li1,
  3. Hao Zhang3,
  4. Chun Luo4,
  5. Dun Yuan1,
  6. Weixi Jiang1,
  7. Junxia Yan4,5
  1. 1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
  2. 2Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
  3. 3Interventional Medical Center, Hunan Province People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410005, China
  4. 4Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South university, Changsha 410078, China
  5. 5Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China
  1. Correspondence to Dr Junxia Yan, Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan 410008, China; 20457456{at}qq.com; Dr Yifeng Li, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China; liyifeng87{at}csu.edu.cn

Abstract

Background The pathogenic mechanism of brain arteriovenous malformation (bAVM) is poorly understood. A growing body of evidence indicates that genetic factors play crucial roles in bAVM. This study examined genetic variants associated with bAVM through quantitative synthesis and qualitative description of literature.

Methods Five databases were searched to gather potentially relevant articles published up to January 2022. STATA 14.0 software was used for statistical analyses. Pooled odds ratios and 95% confidence intervals were calculated with random effect models, and heterogeneity was assessed using the Cochran Q test and quantified with the I2 test. Sensitivity and publication bias were analyzed to test the robustness of the associations. Variants identified in only one study or with great heterogeneity were not suitable for pooling association analysis, and therefore a qualitative systematic review was performed.

Results In total, 30 papers were included in a systematic review involving 4709 cases and 7832 controls, where 17 papers were in a meta-analysis. A suggested association of bAVM was observed with ACVRL1 rs2071219 in the additive model and CDKN2B-AS1 rs1333040 in the recessive and additive models. Other variants of genes that could not be analyzed were summarized by qualitative description. These genes were mostly involved in bone morphogenic protein/transforming growth factor beta (BMP/TGF-β), vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR), and RAS-mitogen activated protein kinase (MAPK) signaling and inflammation.

Conclusions According to our meta-analysis, ACVRL1 rs2071219 and CDKN2B-AS1 rs1333040 were potentially associated with bAVM. Multiple pathological signaling pathways could affect disease development. Future studies should aim to determine the interaction of candidate genes with environmental risk factors and to elucidate detailed mechanisms of action of variants and genes.

1

  • Arteriovenous Malformation
  • Genetic
  • Stroke

Data availability statement

Data are available upon reasonable request. Data not included in this article will be shared when other investigators request to replicate procedures and results. Researchers can contact corresponding author for data access.

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Data availability statement

Data are available upon reasonable request. Data not included in this article will be shared when other investigators request to replicate procedures and results. Researchers can contact corresponding author for data access.

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Footnotes

  • JY and YL contributed equally.

  • Contributors JL: data curation, statistic analysis, investigation, validation, resources and software, writing the original draft, and review and editing. YL: data curation, investigation, validation, resources and software, and funding acquisition. HZ and DY: data curation and investigation. CL: statistic analysis. WJ: project administration and supervision, and funding acquisition. JY: guarantor, project administration and supervision, methodology, funding acquisition, statistic analysis, and writing, review, and editing.

  • Funding This study was supported by grants from the Hunan Province Nature Science Foundation, China (2021JJ30911, 2021JJ31077, 2021JJ31121) and the Financial Science and Technology Project of Hunan Province, China (422000008).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.