NOTCH4 Single-Nucleotide Polymorphism Is Associated With Brain Arteriovenous Malformation in a Chinese Han Population

doi:10.21203/rs.3.rs-1101933/v1

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NOTCH4 Single-Nucleotide Polymorphism Is Associated With Brain Arteriovenous Malformation in a Chinese Han Population

https://doi.org/10.21203/rs.3.rs-1101933/v1

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Background: Brain arteriovenous malformations (BAVMs) are high-flow intracranial vascular malformations characterized by the direct connection of arteries to veins without an intervening capillary bed. It is one of the main causes of intracranial hemorrhage and epilepsy though morbidity is low. Angiogenesis, heredity, inflammation, and arteriovenous malformation syndromes play important roles in BAVM formation. Animal experiments and previous studies have confirmed that NOTCH4 may be associated with BAVM development. Our study identifies a connection between NOTCH4 gene polymorphisms and BAVM in a Chinese Han population.

Methods: We enrolled 150 patients with BAVMs confirmed by digital subtraction angiography (DSA) in the Department of Neurosurgery, Zhujiang Hospital, Southern Medical University from June 2017 to July 2019. Simultaneously, 150 patients without cerebrovascular disease were confirmed by computed tomography angiography/magnetic resonance angiography/DSA. DNA was extracted from peripheral blood and NOTCH4 genotypes were identified by PCR-ligase detection reaction. Chi-square test or Fisher’s exact test was used to evaluate the difference in allele and genotype frequencies between the BAVM group, control group, bleeding, and other complications.

Results: Two single-nucleotide polymorphisms (SNPs), rs443198 and rs438475, were significantly associated with BAVM. No SNP genotypes were significantly associated with hemorrhage and epilepsy. SNPs rs443198_ AA-SNP and rs438475_ AA-SNP may be associated with lower risk of BAVM (P = 0.011, OR = 0.459, 95% CI 0.250–0.845; P = 0.033, OR = 0.759, 95% CI 0.479–1.204).

Conclusion: NOTCH4 gene polymorphisms were associated with BAVM and may be a risk factor in a Chinese Han population.

Neurology

Single-nucleotide polymorphism

brain arteriovenous malformation

NOTCH4

Brain arteriovenous malformations (BAVMs) are high-flow intracranial vascular malformations characterized by the direct connection of arteries to veins without an intervening capillary bed. The rough incidence or detection rate of BAVMs ranges from 1.12 to 1.34 per 100000 per year [1, 2]. BAVMs are usually detected in young people aged 20–40 [3]. Approximately 50% of BAVMs present with intracranial hemorrhage [4]. The other indications include epilepsy (30%), headache, neurological deficit, or no related symptoms [5]. A multicenter non-blind randomized trial of un-ruptured arteriovenous malformations (AVMs) confirmed a spontaneous hemorrhage rate of 2.2% per year (95CI 0.9–4.5) [6]. The pathogeny of BAVM remains undefined. Although the evidence is deficient, it has been considered to be a congenital disease. Angiogenesis, heredity, inflammation, and AVM syndromes contribute to the development of BAVM [9]. Some studies have reported a correlation between genetic factors and BAVM [10]. The relevant genes include SMAD4, ENG, ALK1, NOTCH4, and MMP-3 [15–18].

Vascular endothelial growth factor (VEGF) and the Notch signal pathway play important roles in angiogenesis and differentiation. The Notch signal pathway family contains Notch1–4 receptors and DLL1–3/Jagged-1/2 ligands. Both of them are essential during the whole process of vascular development and differentiation. Ephrin-B2 and Notch family members are expressed in arterial endothelial cells because of their receptors and two ligands [12]. Their functions involve the differentiation of arteries and veins, which are activated by VEGF expression [11].

As a member of the Notch signal pathway, NOTCH4 also acts on angiogenesis and arteriovenous differentiation. The NOTCH4 gene is located in chromosome 6p21.32 and is expressed in endothelial cells. NOTCH4/int-3 and Jagged-1 could promote the differentiation of brain microvascular endothelial cells. An arteriovenous shunt appears after NOTCH4-int3 expression in endothelial cells, which indicates that changes in the NOTCH4 signal could lead to BAVM [8]. An animal study using a transgenic NOTCH4-induced mouse model has reported that the abnormal blood vessel was similar to AVM [13]. Western blotting and immunohistochemistry of BAVM tissue slices show clearly that NOTCH4 is activated in endothelial and smooth muscle cells of humans [14]. All of these point to a possible correlation between BAVM and NOTCH4, but studies about NOTCH4 gene single-nucleotide polymorphisms (SNPs) and BAVM are rare[8], therefore, we decided to start a clinical trial. It is a pioneering study to detect the correlation between a Chinese Han population and NOTCH4 SNPs.

Study cohort

In total, 150 patients with BAVMs were enrolled in our study from June 2017 to July 2019.Nearly half of them were male. The median age was 32 ± 14.8 years (mean 41, range 9–72 years). All of the BAVM patients had undergone diagnostic subtraction angiography (DSA), magnetic resonance angiography (MRA), and computed tomography angiography (CTA) to observe and evaluate AVM nidus. All subjects excluded family history, inheritance history, and history of other cerebral diseases.

The control group included 150 patients with traumatic brain injury in the same period. The median age was 32 ± 14.8 years (mean 41, range 9–72years) and 43.8% of them were male. All of the control group subjects underwent DSA/MRA/CTA to exclude cerebral vascular diseases. After hospital arrival, meticulous clinical examination and a questionnaire about their medical history were conducted. All the subjects involved in the study were confirmed to be from the Chinese Han population. This study conformed to the Declaration of Helsinki and was approved by the Zhujiang Hospital Ethics Committee. All of the subjects signed written informed consent before they joined the study.

Selection and genotyping of NOTCH4 SNPs

Ten SNPs (rs1109771[A/G], rs715299[G/T], rs1044506[G/T], rs3134931[C/T], rs443198[A/G], rs415929[C/T], rs436388[C/T], rs438475[A/G], rs1044507[A/C], and rs915895[C/T]) were selected in the study by using the genetic database Hapmap (http://hapmap.org) and Haploview (http://www.broad.mit.edu/mpg/Haploview). We searched for SNPs with the standard minor allele frequency of <20%, r² > 0.8, and maximum DNA segment size of 250 bp [7]. The SNP genotyping service (polymerase chain reaction (PCR)-ligase detection reaction (LDR)) was supplied by Shanghai Biowing Applied Biotechnology Co. Ltd. Table 1 and Table 2 shows the 10 target gene primer sequences and the target gene probe sequence, respectively. A TIANamp Blood DNA Kit was applied to deal with the blood samples. We used a 20 µl liquid system to run the PCR amplification process (Gene Amp PCR System, Norwalk, CT, USA). The first step of the PCR amplification, denaturation at 95°C for 2 min; the second step, denaturation at 94°C for 30 s, annealing at 56°C for 1 min, extension at 72°C for 1 min, repeated for 40 cycles; final extension at 72°C temperature for 10 min. Multiple agarose gel electrophoresis was applied to observe the electrophoretic effect of the PCR products and to determine the amount of product needed as a template in the LDR. The electrophoresis was mainly to observe whether the PCR is successful but it is almost impossible to distinguish each locus. The LDR was performed after electrophoresis: denaturation at 95°C for 2 min, followed by 40 cycles of denaturation at 94°C for 30 s, and annealing at 50°C for 25 s. Gene mapper (Shanghai,China) was applied for data analysis and genotyping.

Table 1

Comparison of the basic data of the subjects
Group	Patients	Sex (Females/Males)	Age	Hypertensive	Smoking
Control group		78/72	30.55 ± 14.67	14	29
BAVM group	150	70/80	29.75 ± 14.99	9	33
X²/t		0.356	1.284	1.177	0.325
P		0.853	0.203	0.278	0.568

Table 2

Clinical and morphological characteristics of BAVM in the experimental group
Characteristics	Patients
BAVM complication
Hemorrhage	74 (49.3)
Without hemorrhage	76 (50.7)
Epilepsy	24 (16.0)
Without epilepsy	126 (84.0)
BAVM location
Frontal lobe	36 (24.0)
Temporal lobe	29 (19.3)
Occipital and parietal lobe	20 (13.3)
Periventricular area	12 (8.0)
Deep part	14 (9.3)
Brain stem	7 (4.7)
Cerebellum	32 (21.3)
BAVM size
<3 cm	34 (22.7)
3–6 cm	90 (60.0)
>6 cm	26 (17.3)

All SNP loci were assigned with a different length of modification and detection probe. The base group of SNPs was determined by the modification length and detection probe length accordingly.

Statistical methods

Continuous variables were shown by the mean±SD. Hardy–Weinberg equilibrium were calculated by the chi-square test. Differences in the gene polymorphism between BAVM and control subjects were compared by the chi-square test or Fisher’s exact test. Logistic regression analyses were applied for select BAVM-associated SNPs by significant P value, odds ratios (OR), or 95% confidence intervals (95% CIs). We performed three genetic models to estimate the association between the SNPs and the clinical characteristics of the BAVM patients: the dominant model (homozygote rare + heterozygote vs. homozygote common), the recessive genetic model (homozygote rare vs. heterozygote + homozygote common), and the additive model (homozygote rare vs. heterozygote vs. homozygote common). All statistical results are taken from the values of the two-side test, and P < 0.05 was considered to equal statistical significance. All data were analyzed by SPSS20.0 (SPSS Inc., Chicago, IL, USA).

Clinical data of patients

Table 1 and Table 2 shows the clinical data of the study objects. A total of 150 patients with BAVMs and 150 patients in the control group were included in this study. There were 80 males and 70 females in the BAVM group, with an average age of 29.75 ± 14.99; in the control group, there were 72 males and 78 females with an average age of 30.55 ± 14.67. There was no significant difference in the baseline data between the two groups. Among BAVMs, 36 cases were located in the frontal lobe, 29 cases in the temporal lobe, 20 cases in the occipital and parietal lobe, 12 cases in the periventricular area, 14 cases in the deep part, 7 cases in the brain stem, and 32 cases in the cerebellum; 34 cases were smaller than 3 cm³, 90 cases were 3–6 cm³, 26 cases were >6 cm³; 44 cases were located in a functional area; 41 cases were accompanied with deep venous drainage. There were 14, 65, 45, 15, and 11 cases of Spetzler-Martin grade I–V, respectively.

Association analysis of NOTCH4 SNPs and BAVMS

The results of the correlation analysis between NOTCH4 SNPs and BAVMs are shown in Table 3. The relationship between SNPs and BAVMs was verified by the chi-square test or Fisher's exact test. Statistical results showed that rs443198_ AA-SNP and rs438475_ AA-SNP genotype may be associated with a lower risk of BAVM (P = 0.011, OR = 0.459, 95% CI 0.250–0.845; P = 0.033, OR = 0.759, 95% CI 0.479–1.204). The allele frequency of rs443198 was significantly different between the two groups (P = 0.031, OR = 0.697, 95% CI 0.503–0.968). The A locus of rs443198 may be a protective factor for BAVMs.

Table 3

Association analysis between SNPs and BAVM development
SNPs		P	OR (95%CI)	Genotype			Model	OR (95%CI)	P
rs443198	A	G			AA	AG	GG	Dom	0.806 (0.511–1.271)	0.353
BAVM group	36.3	63.7	0.031^*	0.697	19	71	60	Rec	0.773 (0.483–1.236)	0.282
Control group	45.0	55.0		(0.503–0.968)	36	63	51	Add	0.459 (0.250–0.845)	0.011^*
rs438475	G	A			GG	GA	AA	Dom	0.759 (0.479–1.204)	0.241
BAVM group	73.0	27.0	0.367	1.177	76	67	7	Rec	2.611 (1.050–6.496)	0.033*
Control group	69.7	30.3		(0.826–1.678)	76	57	17	Add		1.000

Genotype is not related to the clinical symptoms

We analyzed the relationship between these two SNPs and the symptoms of hemorrhage and epilepsy on the basis that they were associated with BAVMs. Table 4 shows the correlation analysis results of SNPs with symptoms of hemorrhage and epilepsy.

Table 4

Correlation analysis between SNPs and hemorrhage/epilepsy complications
SNPs	Locus frequency%		P	OR (95%CI)	Genotype			Model	OR (95%CI)	P
rs443198	G	A			GG	AG	AA	Dom	0.970 (0.378–2.486)	0.949
Hemorrhage	31.3	18.0	0.856	1.044	30(40.5)	34(45.9)	10(13.5)	Rec	1.116 (0.588–2.120)	0.737
Without hemorrhage	31.7	19.0		(0.654–1.669)	29(38.2)	37(48.7)	10(13.1)	Add	1.105 (0.574–2.128)	0.765
rs443198	G	A			GG	AG	AA	Dom	2.632 (0.842–8.226)	0.087
epilepsy	8.7	7.3	0.303	0.709	6 (25)	14(58.3)	4(16.7)	Rec	0.690 (0.284–1.679)	0.412
Without epilepsy	31.7	52.3		(0.368–1.366)	19(16.4)	57(49.1)	40 (34.5)	Add	1.702 (0.598–4.847)	0.316
rs438475	G	A			GG	AG	AA	Dom	1.333 (0.439–4.048)	0.611
Hemorrhage	34.3	15.0	0.923	1.025	35(47.3)	33(44.6)	6 (8.1)	Rec	0.856 (0.448–1.636)	0.638
Without hemorrhage	35.0	15.7		(0.627–1.674)	37(48.6)	31(40.8)	8(10.5)	Add	0.946 (0.498–1.795)	0.865
rs438475	G	A			GG	AG	AA	Dom	2.875 (0.360–4.962)	0.299
Epilepsy	12.3	3.7	0.186	1.622	14(58.3)	9(37.5)	1 (4.2)	Rec	1.250 (0.509–3.070)	0.626
Without epilepsy	56.7	27.3		(0.788–3.343)	58(46.0)	54(42.9)	14(11.1)	Add	1.641 (0.678–3.973)	0.269
OR, odds ratio; CI, confidence intervals; ^*P value was considered significant at a level of <0.05.

BAVM is an important cause of focal neurological impairment in young people due to intracerebral hemorrhage or epilepsy. Clinical decision-making usually needs to consider the risk of further hemorrhage and the risk of hemorrhage caused by the treatment of cerebral AVM. Prevention of hemorrhage or re-bleeding is still the main prevention and treatment goal of BAVM. Understanding the biological characteristics of the disease can help to identify new biomarkers, predict the future clinical progress of patients, and even promote the development of new treatment strategies. The genetic and biological mechanism of a disease can be determined by studying its genetic factors. Based on this principle, we have studied the genetic polymorphisms of candidate genes to determine whether they may be associated with susceptibility to BAVM and specific clinical features. Nowadays, candidate gene research has become one of the main methods to evaluate the genetic risk of BAVM. Relevant studies have shown that there are more than 900 genes associated with the occurrence of BAVM, among which the expression of more than 300 genes is increased and the expression of more than 500 genes is decreased [19, 20]. In a meta-analysis of a genome-wide association study involving 515 BAVM cases and 1191 control cases, no SNPs were found to be associated with BAVM in the replication cohort after multiple trials. At the same time, several potential candidate genes were selected. These potential candidate genes include ALK1, MMP-3, SP4, NOTCH4, Jag1, egfem1p, CDKAL1, and bnc2 [21]. In this study, we examined whether single nucleotide sites in the NOTCH4 gene are potential genetic risk factors for AVM, AVM bleeding, or AVM associated epilepsy. Our results show that the NOTCH4 gene may play a role in AVM biology. First, we believe that the NOTCH4 gene polymorphism is associated with increased susceptibility to AVMs, so we can consider NOTCH4 as a highly reliable candidate gene. At the same time, our results are different from those reported abroad. The results of foreign studies on BAVM gene polymorphism showed that NOTCH4 SNP rs715299_ A, rs415929_ A, rs1109771_ G significantly increased the risk of BAVM, and rs443198_ TT and rs1109771_ GG has a certain correlation with hemorrhage and secondary epilepsy. Our study did not find genes associated with a higher risk of bleeding and epilepsy, which may be related to population differences.

The polymorphism of NOTCH4 is common in neuropsychiatric diseases, and clinical trials indicate that the most common are related to schizophrenia. A foreign study was conducted on the genotyping of eight polymorphisms in all subjects, and to investigate their correlation with clinical variables. The NOTCH4 gene rs367398 AA/Ag was significantly associated with worse positive and negative symptom scale and the clinical global impression score (CGI) [22]. The results of the study on schizophrenia and NOTCH4 polymorphism in the Chinese Han population in South China also showed that the rs520688_GA-SNP genotype was significantly associated with decreased risk, and rs204993_ AA-SNP genotypes are associated with a higher risk of schizophrenia [22]. In addition, some reports suggest that the Notch4 SNP is associated with lung cancer and inflammatory bowel disease. Based on the fact that haplotype-based markers can improve association efficiency and refine association signals, we estimated the risk of AVM and the polymorphism of the NOTCH4 gene. There is a single marker association between TT-SNP genotypes and the key clinical feature, which is bleeding. It is worth noting that the multiple regression analysis of rs4498_-TT is also a statistically significant predictor of hemorheology, and rs443198_-TT was not previously reported to be associated with bleeding in other diseases. This observation indicates that NOTCH4-SNP may play a special role in AVM related bleeding.

Amyere M sequenced the whole exon of the CM-AVM family and screened a candidate gene from a large number of patients. They found that the EphB4 gene mutation existed in these families, and the performance of these patients was similar to that of AVM caused by HHT, so they suggested that the EphB4–Ras–extracellular signal-regulated kinase (ERK) signaling pathway might be the main cause of AVMs. In recent years, somatic mutation has been a hot topic in AVM research. It has been reported that the KRAS mutation has been detected in endothelial cells from cerebral AVMs, and the expression of mutated KRAS in endothelial cells in vitro induces ERK. The increase of kinase activity increased the expression of genes related to angiogenesis and Notch signaling, and enhanced migration behavior [23]. These processes were reversed by inhibiting MAPK and ERK signaling. They believe that the occurrence of these malformations is caused by KRAS induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. In a study of brain and spinal cord AVMs and detectable tumor-associated somatic mutations, Tao et al. used deep next-generation sequencing of 422 common tumor genes to analyze tissue and paired blood samples. Liquid drop digital PCR was used to identify panel sequencing mutations and additional low mutation frequency relationships. Their results showed that the prevalence of KRAS/BRAF somatic mutations in cerebral and spinal AVM was as high as 87.1%, and there were no other tumor-related replication mutations. The homogeneity and high prevalence of this pathway indicated that a targeted therapy of RAS/RAF pathway inhibitors can be developed without the need for histological-genetic diagnosis [24].

In addition, the importance of SNPs in several genes related to angiogenesis and inflammation and their relationship with the development of AVM were also reviewed [25]. The up-regulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in increased leukocyte recruitment. The increase of metalloproteinase-9 released by leukocytes can damage the vascular wall of BAVM and cause deformed ruptures. Inflammation also affects the proliferation, migration, and apoptosis of endothelial cells by up-regulating the expression of angiogenic factors, which is involved in the changes of the vascular architecture of AVM. The effect of inflammation on the pathogenesis of AVM is also enhanced by some SNPs in proinflammatory cytokine genes, thus increasing their protein level in AVM tissues. So far, many studies have investigated the possible relationship between gene polymorphism and the development of AVM. However, most of these studies focus on the genes that play a role in the inflammatory pathway, while the gene deficiency related to angiogenesis is ignored. At present, the genes related to angiogenesis include ALK1, ANGPTL4, and VEGF. Recently, a new pathway of cerebral AVM has been proposed. Notch signal is located downstream of AVM pathogenic genes such as ALK1 and VEGF. NOTCH4 affects the occurrence of AVM by regulating angiogenesis. Studies have shown that genes encoding angiopoietins (ANGPT1 and ANGPT2) and their receptors Tie-2 play an important role in angiogenesis and vascular stability. In AVM, the Tie-2–angiopoietin system is unbalanced [26]. In addition, the strategy of blocking VEGF and Notch by inhibiting inflammation and angiogenesis has a certain effect on the experimental treatment of BAVM. The research on the participation of metalloproteinase-9 inhibitors in the inhibition of the Notch signal in BAVMs provides key data for the drug treatment of BAVMs, which provide a reference to design and test more specific and effective treatment strategies in the future [27].

In general, clinical research on SNPs requires a large number of subjects to reduce the sampling error in statistics. Unfortunately, only 150 BAVM patients are included in this study because of the low incidence rate. The sample size may reduce the difference of the queue substructure, leading to a false positive association and confounding effect, which makes the results less accurate. Therefore, our research results need to be supported by more data. In addition, BAVM is a complex genetic disease, and the results will be different due to ethnic differences compared with populations in other countries. Moreover, these gene loci lack functional research, so it is difficult to explore further. The occurrence of BAVM and bleeding is affected by both environmental and genetic factors. It is even less possible to accurately judge the influence of these gene loci if we exclude environmental factors and discuss genetic characteristics. This is undoubtedly a common defect in SNP type research. The goal of the future treatment for cerebral AVMs is to establish a disease quantitative model that can predict the occurrence and rupture risk of BAVM. Perhaps the most important gap in BAVM research hinders understanding of the disease because of the lack of a real experimental model. A reliable animal model is key to studying the mechanism of the disease and to test new therapies. At present, there is no real animal model of cerebral AVM. Some models have been proposed and used, but these models are only similar to some aspects of human brain AVMs, not all aspects [28–29]. Therefore, more advanced experimental techniques, new statistical models and animal models, and larger research sequences will contribute to the progress of this series of studies. In conclusion, our results have preliminarily confirmed the relationship between NOTCH4 polymorphism and cerebral AVM in a Chinese Han population. However, we have not yet explored its downstream regulatory mechanism, so more in-depth research is needed on how the gene affects the occurrence of BAVM. Our ultimate goal is to find a highly consistent pathway and develop targeted therapy for pathway inhibitors to prevent and treat early cerebral AVMs in asymptomatic individuals or adolescents.

NOTCH4 is associated with the generation of BAVM. The NOTCH4 SNP may be a risk factor for BAVM.

Acknowledgments

We thank the blood donors and all the medical workers who generously supported us in the study.

Funding

The study was supported by grants from the Natural Science Funds of China (No.81400943), the National Key Clinical Specialty; the Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, and the Department of Neurosurgery, Zhujiang Hospital, Southern Medical University in China.

Conflict of Interests

The authors declare that they have no conflict of interests.

Availability of data/materials

The original data of the study is not publicly available because consent was obtained to provide only cumulative anonymized data. All the data was recorded and regulated by the corresponding author. The data used or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contribution

Author contributions to the study and manuscript preparation were as follows. Conception and design: ZM,JBZ and XYH. Collection of data: JBZ and ZM. Statistical analysis:ZM, JBZ and XYH. Drafting the manuscript: ZM,JBZ and HYF. Revision of the manuscript: all the authors. All the authors approved the final manuscript.

Ethical recognition and informed consent

The study was approved by the Ethical Committees of Zhujiang Hospital of Southern Medical University. All participants volunteered to join in the project after they were informed of the purpose and significance of the study and signed the informed consent. The blood samples obtained from this study were from volunteers who signed informed consent.

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NOTCH4 Single-Nucleotide Polymorphism Is Associated With Brain Arteriovenous Malformation in a Chinese Han Population

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Background

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Study cohort

Statistical methods

Results

Clinical data of patients

Genotype is not related to the clinical symptoms

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1