Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation

Abstract

BackgroundThe 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.MethodsFive 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.ResultsIn 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.ConclusionsAccording 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

Methodological quality assessment of genetic studies on brain arteriovenous malformation related hemorrhage: A cross-sectional study

“…VEGF is highly expressed in endothelial cells of bAVM, especially in ruptured bAVM lesions ( McDonald et al, 2015 ). Activation of this pathway could promote endothelial cell migration and recruitment of smooth muscle cells, resulting in pathological angiogenesis ( Liu et al, 2022 ). A recent study using mouse bAVM models demonstrated that an elevated VEGF level could contribute to bAVM hemorrhage by exposure to variable degrees of higher intraluminal flow and hypertension in the venous system ( Cheng et al, 2019 ).…”

“…Additionally, it has been reported that these genes can increase the expression of inflammatory cytokines in bAVM tissues, leading to endothelial dysfunction and malformation of vasculature (Krithika and Sumi, 2021). It has been shown that inflammatory infiltration can be observed even in unruptured bAVM lesions, proving the role of inflammation in the development and rupture of the disease (Liu et al, 2022). As the disease progresses, endothelial lesions would weaken the vasculature, and once patients are exposed to a trigger, an acute hemorrhage event occurs.…”

Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations

“…100 More than 1200 dysregulated genes have been identified in human bAVM tissue. 101,102 The functions of these genes are directly linked to inflammation, angiogenesis, vasculogenesis, cell migration, and the cytoskeletal system. 103…”

Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease

“…Several pathogenic gene variants in the TGF-β pathway have been identified through genome-wide association studies (GWAS) and whole exome trio sequencing. These variants are linked to small vessel ischemic strokes, intracerebral hemorrhages, and sporadic brain arteriovenous malformations (AVMs) [110,111]. Increased expression of TGF-β1 has been found in the brain tissue after ischemic stroke, as well as in hereditary amyloidosis-Dutch type with cerebral hemorrhage [112].…”