Association Between the miR-100 rs1834306 A&gt;G SNP and Susceptibility to Vascular Malformation in Southern Chinese Children

doi:10.21203/rs.3.rs-2719333/v1

Background:Vascular malformation was related to genes and resulted in functional and morphologic anomalies. Genetic variations affecting development of vessel endothelial cells are unclear. Therefore, this study aimed to investigated the potential value of miR-100 rs1834306 A>G SNP as a marker of susceptibility to vascular malformation.

Methods:In this case–control study in southern Chinese children, we collected samples from 1158 controls and 1113 patients with vascular malformation. TaqMan genotyping of miR-100 rs1834306 A>G was performed by real-time fluorescent quantitative polymerase chain reaction.

Result:Multivariate logistic regression analysis showed that there was no significant association between the presence of the miR-100 rs1834306 A>G polymorphism and susceptibility to vascular malformation by evaluating the values of pooled odds ratios and 95% confidence intervals. Similarly, among different sites, rs1834306 A>G was also not associated with vascular malformation.

Conclusion:Our results suggest that the miR-100 rs1834306 A>G polymorphism is not associated with susceptibility to vascular malformation in southern Chinese children. These results need to be further confirmed by investigating a more diverse ethnic population of patients with vascular malformation.

vascular malformation

microRNA

polymorphism

Vascular malformation (VM) refers to a group of congenital defects in vascular development that manifest as diffuse or local structural abnormalities later in life, and its etiology is unknown [1]. VM results in functional and morphologic anomalies of the affected vascular areas with consequent hemodynamic aberrations [2]. As a result, VM patients are symptomatic, although some lesions remain quiescent for many years. Recent studies have proven that genetic mutations are responsible for VM pathogenesis in many patients [3]. Vascular malformation includes artery malformation, venous malformation, capillary malformation and lymphatic malformations [4]. Venous malformation is the most common form of congenital VM [5]. VM in different areas results in different symptoms, such as pain and swelling when it occurs in the limbs and disfigurement when it occurs in the face. VM can be life threatening when it occurs in important organs such as the pharynx, larynx, brain and heart [4, 6]. The disease has negative effects on patients’ daily lives, and identification of the main molecules involved in VM is urgent for improving clinical outcomes. A growing number of genes and genetic pathways that play a role in endothelial cell proliferation have been confirmed to be related to the pathogenesis of VM [7–10]. However, the exact mechanism underlying VM is not currently clear. Most VMs are caused by mutations in genes involved in one of the following three signalling pathways: PIK3CA, MAPK and G-protein-coupled receptor signaling [11].

Methylation is significantly correlated with the occurrence of VMs [11–13]. The phenotypic spectrum of somatic mutations is wide and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. It has been shown that in vascular endothelial cells, methyl-binding proteins bind to methylated promoters of eNOS and vascular endothelial growth factor receptor 2 (VEGFR2) [14]. Ablation of methyl-binding proteins in these cells leads to activation of eNOS and VEGFR2 gene expression and stimulates the proangiogenetic signaling pathway [13]. However, the role of epitranscriptomics in this pathogenesis requires further research.

Epitranscriptomics refers to RNA modifications or functional alterations in the transcriptome that do not change the ribonucleotide sequence [15]. MicroRNAs (miRNAs) are a class of single-stranded, small molecule RNAs that are derived from noncoding regions of DNA [15]. These miRNAs can act as oncogenes or tumor suppressors to regulate a variety of biological processes, such as development, inflammation, and tumorigenesis [16]. miR-100 is a potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interactions in vitro and in vivo [17]. Leonhard [18] reported that neovascularization during graft-versus-host disease is regulated by miR-100 [19]. Grundmann [20] proved that miR-100 has an antiangiogenic function and re-presses mTOR signaling in endothelial and vascular smooth muscle cells. Recent re-search has revealed that local miR-100 expression is inversely correlated with patient inflammatory cell levels [17]. Genetic variations, also known as polymorphisms, in miRNA genes play an important role in and have potential value for identifying high-risk individuals and diagnosing patients early. Developing interventions that target these poly-morphisms can reduce the development and susceptibility of disease. However, the polymorphisms of miR-100 have not been investigated in VM case–control studies. A poly-morphism of miR-100 may affect the migration and proliferation of embryonic endothelial cells, and may be an underlying cause of VM. Therefore, we aimed to investigate the association of the miR-100 rs1834306 A > G single nucleotide polymorphism (SNP) and the risk of VM in southern Chinese children in a case–control study.

2.1. Patients

Our study was prospectively planned and conducted as a case–control study. We included southern Chinese children with venous malformation and healthy controls who were recruited from the Guangzhou Women and Children’s Medical Center from February 2010 to November 2015. The healthy controls were children who were matched geo-graphically and ethnically with the children with venous malformation and had no prior history of VM. This study was approved by the institutional review board of Guangzhou Women and Children’s Medical Center (Ethical approval No. 201943800). All patients were diagnosed with venous malformation via physical examination and clinical imaging diagnosis. Clinical information was collected from medical records, and all subjects or their guardians signed informed consent forms.

On the basis of our previous criteria, in the present case‒control study, we isolated the potential rs1834306 A > G polymorphic locus of miR-100. Using a TIANamp Blood DNA Kit (DP348; TianGen Biotech Co., Ltd., Beijing, China) and TIANquick FFPE DNA Kit (DP330; TianGen Biotech Co., Ltd.), DNA was extracted from peripheral blood leukocytes and paraffin-embedded intestine samples from all participants. The DNA samples were diluted to 5 ng/mL in 96-well plates and stored at -20°C for later use. They were then add-ed to a TaqMan Genotyping PCR PreMix (probe (FP211); TianGen Biotech Co., Ltd.) in 384-well plates. Real-time fluorescent quantitative polymerase chain reaction was used to genotype the miR-100 r rs1834306 A > G SNP. At least 10% of samples were randomly selected for repeated genotyping, and the same results were obtained.

2.2. Statistical Analysis

Differences in demographic characteristics and distribution of genotype frequency be-tween patients with VM and healthy controls were assessed using the bilateral χ2 test. The Hardy–Weinberg equilibrium was used to assess the genotype frequencies of the good-ness-of-fit χ2 test in the healthy controls.

Measurement data are presented as the mean ± standard deviation. Multivariate logistic regression was used to adjust for the effects of age and sex. The association between the miR-100 SNP and susceptibility to vascular malformation was estimated by multivariate analysis. Logistic regression analysis using odds ratios (ORs) and 95% confidence intervals (CIs) was performed.

Furthermore, stratified analyses were performed to calculate different subtypes of VM based on the VM site of the limbs. All statistical analyses and tests were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). Statistical significance was set at P < 0.05.

3.1. Baseline Demographics

We studied 1113 southern Chinese children with VM (mean age: 68.98 ± 37.08 months; 54.90% boys) and 1158 healthy controls (mean age: 22.22 ± 19.98 months; 56.82% boys).

3.2. Association of the miR-100 rs1834306 A > G SNP with susceptibility to VM

Using real-time fluorescent quantitative polymerase chain reaction, we successfully genotyped the miR-100 rs1834306 A > G SNP in 1113 patients and 1158 controls. The distribution of the genotype frequency of the miR-100 rs1834306 A > G SNP was consistent with the Hardy–Weinberg equilibrium (rs1834306 A > G, P = 0.120) in healthy controls. We found that the genotype results in patients with VM were not significantly different com-pared with those of the healthy controls. Therefore, none of the rs1834306 genotypes were associated with susceptibility to VM (Table 1).

Table 1

Association between *miR-100* rs1834306 A > G polymorphisms and vascular malformation susceptibility.
Genotype	Cases (N = 1113)	Controls (N = 1158)	P ¹	Crude OR (95% CI)	P	Adjusted OR (95% CI) ²	P^2b
rs1834306 A > G (HWE = 0.120)
AA	365 (32.79)	380 (32.82)		1.00		1.00
AG	537 (48.25)	589 (50.86)		0.95 (0.79–1.14)	0.581	0.98 (0.77–1.25)	0.874
GG	211 (18.96)	189 (16.32)		1.16 (0.91–1.48)	0.226	1.19 (0.86–1.64)	0.286
Additive			0.362	1.06 (0.94–1.19)	0.362	1.07 (0.92–1.26)	0.379
AG/GG	748 (67.21)	778 (67.18)	0.992	1.00 (0.84–1.19)	0.992	1.03 (0.82–1.30)	0.796
AA/AG	902 (81.04)	969 (83.68)		1.00		1.00
GG	211 (18.96)	189 (16.32)	0.099	1.20 (0.97–1.49)	0.100	1.21 (0.91–1.60)	0.199

OR, odds ratio; CI, confidence interval, HWE, Hardy-Weinberg equilibrium.

¹ χ² test for genotype distributions between vascular malformation patients and healthy controls.

² Adjusted for age and gender.

3.3. Stratification Analysis of the Risk between the miR-100 rs1834306 A > G SNP and Different VM Sites

According to different VM sites, VM was divided into 6 different subtypes, including head, neck, trunk, upper limbs, lower limbs and multiple vascular malformations. After adjusting for age and sex, we found that there were no significant associations between the miR-100 rs1834306 A > G SNP and the six VM subtypes (Table 2). This finding suggests that the miR-100 rs1834306 A > G SNP is not associated with susceptibility to VM.

Table 2

Stratification analysis for the association between the *miR-100* rs1834306 A > G SNP and vascular malformation susceptibility (by site).
Variables	rs1834306 (cases/controls)		Crude OR	P	Adjusted OR 1	P 1
	AA/AG	GG	(95% CI)		(95% CI)
Head	244/969	64/189	1.35 (0.98–1.85)	0.066	1.38 (0.95–2.01)	0.092
Neck	24/969	3/189	0.64 (0.19–2.15)	0.471	0.71 (0.17–2.88)	0.629
Trunk	107/969	27/189	1.29 (0.83–2.03)	0.262	1.07 (0.59–1.92)	0.827
Upper limbs	181/969	41/189	1.16 (0.80–1.69)	0.432	0.98 (0.59–1.62)	0.939
Lower limbs	275/969	57/189	1.06 (0.77–1.47)	0.714	1.05 (0.66–1.67)	0.844
Multiple	71/969	19/189	1.37 (0.81–2.33)	0.241	1.15 (0.57–2.34)	0.692

OR, odds ratio; CI, confidence interval.

¹Adjusted for age and gender.

Although genetic data from numerous studies suggest that genetic abnormalities trigger VM pathogenesis, the exact molecular pathways responsible for the development of these lesions remain to be elucidated [3, 21, 22]. In our case–control study of southern Chinese children, we investigated the association between a miR-100 SNP and susceptibility to VM. To the best of our knowledge, the miR-100 rs1834306 A > G SNP has not been examined in any previous studies on VM. Our study showed that miR-100 rs1834306 A > G SNP was not significantly associated with susceptibility to VM in southern Chinese children.

Genetic mutations affecting proliferation, migration, adhesion, differentiation, and survival of endothelial cells, as well as integrity of extracellular matrix, are believed to con-tribute to the pathogenesis of VM. An increased number of genetic mutations have been discovered in vascular anomalies via targeted deep sequencing. For example, both non-complicated cutaneous capillary malformation and capillary malformation associated with Sturge‒Weber syndrome were found to have the same GNAQ mutations [3, 23–25]. Similarly, mutations in AKT1, AKT2, and AKT3 have also been discovered in patients with megaloencephaly and venous and capillary malformation [26, 27]. Many studies have investigated the potential functional genetic variation sites and their genetic susceptibilities to VM. Cottrell et al. [28] suggested that PIK3R1 variation underlies vascular malformations and over growth. AlOlabi et al. [29] discovered multiple mosaic-activating variants in 4 genes, KRAS, NRAS, BRAF, and MAP2K1 of the RAS/MAPK pathway, which is commonly activated in cancer and responsible for germline RASopathies. Furthermore, PIK3CA mutation was also discovered in patients with congenital lipomatous overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies (CLOVES) syndrome, capillary vascular malformation of the lower lip (CLAPO) syndrome, capillary malformation with megalencephaly, Klippel-Trenaunay syndrome, or mucocutaneous venous malformations [30–32]. These studies indicate that SNPs may affect the expression and function of target genes and may contribute to VM susceptibility. Investigating the effect of SNPs and genetic mutations on the pathogenesis of VM will contribute to a better understanding of the etiology of this disease.

A growing amount of research has shown that noncoding RNAs are potential markers of disease risk and prognosis in VMs [33, 34]. MiR-21 expression is markedly decreased in skin specimens from patients with VM compared with that of skin specimens from healthy individuals, and miR-21 positively regulates the expression of collagens in human umbilical vein endothelial cells (HUVECs) and shows a positive association with the TGF-β/Smad3 pathway in VM tissues [35]. MiR-145 expression was positively correlated with TGF-β expression and perivascular α-SMA cell coverage in VM tissue samples [36]. Moreover, miR-18a-5p was reported to regulate the activation of P53 signaling pathway constituents and consequently regulate proliferation, migration, invasion and angiogenesis [37].

Nonetheless, whether miR-100 is involved in the pathogenesis of VM has yet to be determined. At present, several studies have concentrated on the effect of miR-100 on the vasculature. Yu et al. [38] discovered that miR-100, along with other miRNAs, exerts considerable influences on circulatory systems in cancellous bone by targeting cytokines and enzymes such catalase, fibroblast growth factor and nerve growth factor. Furthermore, miR-100 plays a role in disrupting the formation of vessels by negatively regulating angiopoietin 2, which inhibits encapsulated tumor clusters [39]. Moreover, overexpression of miR-100 attenuates endothelial cell dysfunction by targeting HIPK2 after hypoxia and reoxygenation treatment [40]. Grundmann et al. [20] proved that miR-100 has an antiangiogenic function and represses mTOR signaling in endothelial and vascular smooth muscle cells. Collectively, these reports raised the question of whether miR-100 can directly regulate the migration or differentiation of endothelial cells in the pathogenesis of VM. However, our results are not completely consistent with those of previous studies. Previous studies concentrated on the effect of miR-100 on rats or in vitro experiments, while our study used a population analysis. As a result of the possible differences in allele frequencies and SNP-mediated allelic imbalance among different populations, only the rs1834306 A > G SNP from the miR-100 gene was selected for association analysis in the current study. Additional gene polymorphisms should be further investigated in future studies.

In summary, the miR-100 rs1834306 A > G SNP is not associated with the risk of VM in southern Chinese children. The role of other SNPs in pathogenesis of VM needs to be further examined. Future research should study target genetic variants identified in VM to identify their role and clinical effect in VM pathogenesis. These investigations may ultimately lead to better screening programs and prevention of VM.

VM	vascular malformation
PIK3CA	phosphatidylinositol 3-kinase catalytic subunit alpha.
MAPK	Mitogen-activated protein kinase
eNOS	endothelial nitric oxide synthase
VEGFR2	vessel endothelial growth factor receptor 2
miRNAs	microRNAs
ORs	odd ratios
SNP	Single Nucleotide Polymorphism
GNAQ	G protein guanine nucleotide binding protein alpha subunit q
HUVECs	human umbilical vein endothelial cells
HIPK2	Homeodomain-Interacting Protein Kinase 2

Acknowledgments

Thank Clinical Biological Resource Bank of Guangzhou women and children’s medical center for providing the clinical sample.

Disclosure

The authors have nothing to disclosure.

Author’s contributions

Conceptualization, Zhenyin Liu; Data curation, Xi Lin; Formal analysis, Guitao Wu; Funding acquisition, Zhenyin Liu; Methodology, Zhenyin Liu, Guitao Wu and Xi Lin; Project administration, Zhenyin Liu; Resources, Hua Jiang; Writing – original draft, Guitao Wu; Writing – review & editing, Guitao Wu, Xi Lin and Hua Jiang.

Funding

This research has been funded in Guangzhou Women and Children's Medical Center Hospital Fund, Fund No.: IP-2019-015.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study received the agreement of the Ethics Committee in Children's Medical Center and was conducted according to the principles expressed in the Declaration of Helsinki of 1975, as revised in 2001. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

There are no competing interests to declare.

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No competing interests reported.

Association Between the miR-100 rs1834306 A>G SNP and Susceptibility to Vascular Malformation in Southern Chinese Children

Status:

Version 1

Abstract

1. Introduction

2. Methods

2.1. Patients

2.2. Statistical Analysis

3. Results

3.1. Baseline Demographics

3.2. Association of the miR-100 rs1834306 A > G SNP with susceptibility to VM

3.3. Stratification Analysis of the Risk between the miR-100 rs1834306 A > G SNP and Different VM Sites

4. Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1