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Gene & Protein in Disease Genetics of arteriovenous malformations

in bAVM, which were however less common than KRAS been explored and reported in the literature to be associated
mutations . with increased risk of bAVM rupture in patients.
[33]
Many AVM is sporadic and SNPs in some specific Estimating the risk of ICH and determining the costs
genes have been shown to be responsible for the sporadic and benefits of intervention tend to be a challenge when
susceptibility to bAVM . SNPs in the following genes: IL-6, managing bAVM. Pawlikowska et al. demonstrated
[75]
IL-1, IL-1β, tumor necrosis factor (TNF), transforming that polymorphism in IL-6 could be linked to ICH in
growth factor-beta 2 (TGFRB2), matrix metallopeptidase bAVM . According to Pawlikowska et al., bAVM patients
[80]
3 (MMP3), angiopoietin like 4 (ANGPTL4), and VEGFA homozygous for the IL-6–174G allele (GG genotype) had a
have been linked to bAVM with IL-6, TNF and activin greater risk of presenting with ICH (OR [odds ratio], 2.62,
receptor-like kinase-1 (ACVRL1) being the most frequently P=0.003) than IL-6–174C carriers .
[80]
linked [54,76,77] . SNPs in these genes increase the inflammatory The support for IL-6 as a genetic risk factor has been
response to provocation and result in an overabundance of further reiterated with primary research data. Chen
pro-inflammatory cytokines, which in turn exacerbates the et al. also demonstrated that the GG genotype of IL-6
inflammatory response, recruits leukocytes, and activates
the endothelial cells of the AVM . This eventually leads to was also associated 57with increased gene expression
[76]
increased vascular injury and angiogenesis, which result in of IL-6 compared to the GC and CC genotypes. This
the formation and expansion of AVM [76,78] . Li et al. showed homozygous genotype was associated with increased risk
[81]
that de novo germline mutations in genes including of hemorrhage . The clinical utility of these findings
endoglin (ENG), junction plakoglobin (JUP), exophilin 5 demonstrates that diagnostic genotyping in patients
(EXPH5), and endothelial PAS domain-containing protein with bAVM for IL-6 could be useful in determining the
1 (EPAS1) were found to be potentially related to sporadic need for a patient to have early surgical intervention or
bAVM pathogenesis in a study that performed whole other preventative therapeutic options. The correlation
exome sequencing of case-unaffected-parental bAVM trios between increased IL-6 protein in bAVM tissue
(Table 1) . postoperatively and risk of hemorrhage in bAVM stems
[79]
from the increased expression of MMP in bAVM .
[81]
5. Genetic considerations of AVM and MMPs are known to be involved in vascular remodeling,
[81]
rupture adaption, and repair . In animal models, it was found
that IL-6 activated and induced expression of MMP-3
The most devastating clinical outcome of AVM occurs and MMP-9, and subsequently increased proliferation
secondary to bAVM rupture resulting in intracerebral and migration of cultured human cerebral endothelial
hemorrhage. There are several genetic factors that have cells . Therefore, increased levels of IL-6 in humans
[81]
may be involved in the upstream regulation of MMP-3
Table 1. Top candidate genes associated with AVM and MMP-9, which would lead to instability of the blood
development and pathogenesis vessels . Furthermore, IL6 expression may modulate
[81]
References Genes Mutations and their impacts downstream inflammatory and angiogenic targets that
Couto et al. [50] MAP2K1 Gain-of-function mutation, MAP2K1- result in ICH. Thus, our genetic understanding of IL6
K57N; activates RAS/MPK signaling and its protein products and their involvement in bAVM
Revencu et al. [52] RASA1 Activates RAS GTPase growth and eventual ICH rupture can provide essential
Amyere et al. [96] EPHB4 Loss-of-function mutation; dysregulates clinical information, which can aid in diagnostic testing
vascular development and causes vascular and risk stratification.
defects SNPs in TNF-α and apolipoprotein E (APOE) have also
Fish et al. [69] KRAS Gain-of-function mutation; involved in been associated with AVM rupture. Kim et al. reported
constitutive MAPK/MEK/ERK signaling TNF-α as a genetic risk factor for AVM rupture . In a
[30]
Hongo et al. [54] ALK-1 Loss-of-function mutation; dysregulates cohort of 280 patients with AVM, the A allele of the TNF-
TGF-β/BMP signaling α–238G > A promoter SNP was associated with new
Sturiale et al. [77] IL-6 Contributes to inflammatory processes, hemorrhage . They reported an HR of 4.0 (95% CI = 1.3
[30]
IL-1 including leukocyte recruitment and
IL-1β endothelial activation – 12.3; p = 0.015) with adjustment of initial presentation
Hongo et al. [54] BRAF Activates RAF/MEK/ERK (MAPK/ERK) with hemorrhage, age and race/ethnicity. Pawlikowska
signaling et al. reported on APOE ε2, but not APOEε4 allele, being
Abbreviations: IL: Interleukin; AVM: Arteriovenous malformations; associated with new hemorrhage (n = 284) in the natural
TGF-β: Transforming growth factor beta 1; BMP: Bone morphogenetic course of AVM cases, with an adjusted HR of 5.1 (95%
[82]
protein. CI = 1.5 – 17.7; p = 0.01) . In addition, both APOEε2

Volume 2 Issue 2 (2023) 7 https://doi.org/10.36922/gpd.0312