Biochemical and Biophysical Research Communications xxx (2018) 1e6

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Biochemical and Biophysical Research Communications

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A potential risk factor of essential hypertension in case-control study:

Circular RNA hsa_circ_0037911
Xingjie Bao a, 1, Shuying Zheng a, 1, Shuqi Mao b, 1, Tianlun Gu a, Shike Liu c, Jihan Sun d,
Lina Zhang a, *
a
Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Medicine School of Ningbo
University, 818 Fenghua Road, Ningbo, Zhejiang Province, 315211, China
b
Beilun District Center for Disease Control and Prevention, Ningbo, Zhejiang, China
c
Ninghai County Center for Disease Control and Prevention, Ningbo, Zhejiang, China
d
Department of Clinical Medicine, School of Medicine, Hang Zhou Normal University, Hangzhou, China

a r t i c l e i n f o a b s t r a c t

Article history: Background: Essential hypertension (EH) is a high prevalence with multifactorial diseases. Human
Received 6 March 2018 studies on the impact of genes on this disease are just in the initial stage, the mechanism of gene
Accepted 7 March 2018 regulation is still remains unclear. Circular RNAs (circRNAs) as a continuous cycle of covalent closure, RNA
Available online xxx
molecules added to the 30 -50 end covalently bound by the formation of incidental event. CircRNAs may be
an important biomolecule in revealing the molecule regulate mechanisms of EH.
Keywords:
Methods: The circRNAs were selected and validated with qRT-PCR followed. Our experiment was con-
circRNA
ducted with case-control studies among 200 EH participants. The t-test was used to evaluate the
Essential hypertension
hsa_circ_0037911
different expression of circRNAs and miRNAs, the significance of which was set as p < 0.05.
Gene expression Results: The hsa_circ_0037911 expression level in EH cases were significantly higher than healthy con-
Biomarker trols (p ¼ 0.005). There was still important significance when adjusted by logistic regression (adjusted
p ¼ 0.026). We also found that hsa_circ_0037911 was an effective marker of EH (area under
curve ¼ 0.627; p ¼ 0.002). The levels of hsa_circ_0037911 were significantly differences in gender, BMI,
smoking and drinking among EH cases. There was a positive correlation between Serum creatinine (Scr)
and hsa_circ_0037911.
Conclusions: Our findings suggested that higher expression hsa_circ_0037911 may be key circRNAs for
EH development by changing the concentration of Scr and could be a stable biomarker for early diagnosis
of EH.
© 2018 Elsevier Inc. All rights reserved.

1. Introduction
Essential hypertension (EH) is a complex multifactorial disorder
that is one of the most common diseases among human cardio-
vascular system. The symptoms of EH are not obvious, so EH is
known as a silent killer [1]. It is a global public crisis, and the
prevalence rate of China is 32.5% [2], and about one third Chinese
adults suffered EH. Although some of environmental risk factors for
hypertension, including age, gender, region and socioeconomic
status are reported [3e5], there are still considerable uncertain
* Corresponding author. Correspondening author.
E-mail address: zhanglina@nbu.edu.cn (L. Zhang).
1 serve as a template for virus and virus replication, as an
These authors contributed equally to this work.
about the risk of EH, e.g. considerable of gene interactions. We also
lack satisfactory biomarkers for early detection of EH. Therefore, it
is necessary to determine the molecular characteristics and
searching new diagnosis biomarkers of hypertension in current
research.
Circular RNA (circRNA) is generally presented as a special class
of endogenous RNAs characterized by lacking both a 50 cap and a
30 tail [6]. CircRNAs were thought to be a mysterious endogenous
class of RNA transcribed from introns and exons [7,8], and were
resistant to degradation caused by ribonuclease (RNase) or
exonuclease.
Some studies have found that circRNAs expression were more
abundant than classical mRNA, participate in the RNA - protein
complex formation or RNR - RNA regulation network [9,10], and can

https://doi.org/10.1016/j.bbrc.2018.03.059
0006-291X/© 2018 Elsevier Inc. All rights reserved.

Please cite this article in press as: X. Bao, et al., A potential risk factor of essential hypertension in case-control study: Circular RNA
hsa_circ_0037911, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.03.059
2 X. Bao et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6
intermediate in RNA processing reactions, as cis-acting transcrip-
tional regulators such as snoRNAs and miRNA sponges [11].
Although recent studies indicate that circRNAs function partici-
pated in the development of some healthy diseases [12], little is
known about their role in EH.
Hsa_circ_0037911is a circular RNA containing 4 exons by a
length of 346nt splicing sequence (http://circrna.org/). The gene of
circular RNA is located in the region from 11988810bp to
11991892bp of chromosome 16, and the association gene symbol is
GSPT1 (G1 to S phase transition 1 gene). According to the bioin-
formatics analysis of the CircBase database, hsa_circ_0037911 is
one of the circRNAs that may be associated with EH. In the present
study, we chose it as the targeted circRNA for EH.
In this case-control study, it's the first time that we verified the
expression levels of hsa_circ_0037911 in whole blood of partici-
pants is associated with EH. In addition, this is consistent with
result of bioinformatics analysis of the CircBase database. Then, we
explore the expression levels of hsa_circ_0037911 in EH group and
control group, and the potential relationship between its expres-
sion levels and clinical indicators. Moreover, we have constructed a
receiver operating characteristics (ROC) curve to analyze the
sensitivity of hsa_circ_0037911in diagnosis of EH. Our data suggest
that hsa_circ_0037911 plays a crucial role in the development of EH
and may be a potential biomarker for hypertension screening and
prevention.
2. Materials and methods
2.1. Population and samples collection
A total of 100 EH cases and 100 sex- and age- (±3 years) match
healthy controls were obtained from physical examination center
of Ningbo Yinzhou People's Hospital, China between September
2017 and January 2018. All research subjects were evaluated by the
exclusion and inclusion criteria, and agreed with understanding
and informed the written consent before being enrolled into the
study. EH cases were defined as hypertensive based on systolic
blood pressure (SBP)  140 mmHg and/or diastolic blood pressure
(DBP)  90 mmHg in accordance with the 2016 guidelines for the
diagnosis and management of hypertension in adults [13]; controls
with SBP < 120 mmHg and DBP < 80 mmHg. Two hundred cases
had no history of secondary hypertension, diabetes mellitus,
myocardial infarction, stroke, renal failure, drug abuse or other
serious diseases, no family history of hypertension in the first-
degree relatives, and did not receive treatment for hypertension.
Following 12 h overnight fasting, blood samples gathered from the
antecubital vein using ethylenediaminetetraacetic acid (EDTA) and
stored at 80  C. In order to determined candidate circRNAs, we
first collected in Ningbo Seventh Hospital on five pairs of newly
diagnosed EH and non-EH whole blood samples using the Agilent
human circRNA microarray. In the validation phase, the real-time
quantitative reverse transcription-polymerase chain reaction
(qRT-PCR) was performed to analyze the difference of two circRNAs
(hsa_circ_0037911, hsa_circ_0002161) between EH group and
control.
2.2. Biochemical analysis and total RNA extraction
Biochemical variables were measured using an Olympus
AU2700 High-Volume Chemistry-Immuno Analyzer (Tokyo, Japan).
A TRIzol kit (TransGen Biotech corporation, Beijing, CHN) was used
to extract total RNA from peripheral blood samples. The concen-
tration and purity of extracted RNA was measured by an ultramicro
nucleic acid ultraviolet tester (NanoDrop4002; Thermo Fisher Sci-
entific, Waltham, MA, USA).
Please cite this article in press as: X. Bao, et al., A potential risk factor of essential hypertension in case-control study: Circular RNA
hsa_circ_0037911, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.03.059
2.3. Quantitative RT-PCR
QRT-PCR was performed with the GoTaq® Real-Time PCR Sys-
tems reagent kit (Promega, Beijing, China) following the manu-
facturer's instructions. The sequences of the divergent
primersofhsa_circ_0002161 were: 50 - CGTA-
GATGCTGGCAAGTCAAC-30 and50 - CCCTGGCTCTGCTTCACTTATT-3’;
hsa_circ_0037911 were 50 -ACCATTGGAGGACAAATAATCACC-30 and
50 - GTTCTGAAAGTTCCATGCTAACAG-30 were performed to detect
the target genes (Table S1). The primer sequences of the glyceral-
dehyde-3-phosphatedehydrogenase (GAPDH) as internal control
for circRNAs when it was amplified. All primers were synthesized
by Invitrogen (Shanghai, China). The reaction conditions of circR-
NAs were as follows: 95 Cfor 2 min, and 40 cycles of 95  C for 5 s,
58 Cfor 30 s and 72  C for 30 s. All of the quantitative PCR reactions
were 3 replications for each. Furthermore, the single-peak of
melting curve suggested the specificity of the PCR products.
2.4. Statistical analysis
All experimental data were analyzed in SPSS software 19.0 (SPSS
Inc., Chicago, IL, USA) and GraghPad Prism 5.0 (GraphPad Software,
La Jolla, CA, USA). The expression levels of circRNAs were analyzed
by the DCt method [14], and the GAPDH gene was considered to be
the normal expression level of target genes. Differences of two
circRNAs levels between EH group and control group, and contin-
uous variables data were assessed using t-tests. Categorical vari-
ables (sex, smoking and drinking status) were using pearson chi-
square. Logistic regression was constructed to analyze the in-
teractions of circRNAs and other variables and to adjust for con-
founding factors. The ROC curve was conducted to investigate the
diagnostic value. A two-side p < 0.05 indicated statistical
significance.
3. Results
3.1. Demographic and clinical data for study subjects
In the study, a total of 200 participants aged between 30 and 70
years including 100 EH group and 100 gender- and age-matched
(±3 years) non-EH group were enrolled in the present study. In
Table 1, the clinical characteristics and demographic were within
normal ranges. Age and gender were no significant differences
between patients and controls. Body mass index (BMI) (t ¼ - 3.27,
p ¼ 0.001) and Serum creatinine (Scr) (t ¼ 0.006, p ¼ 0.0331) did
significant differ between EH and non-EH groups.
3.2. Validation of circRNA in essential hypertension
We selected two up-regulated circRNAs according to the result
of microarray to explore the association of circRNA and EH. Hsa_-
circ_0002161 and hsa_circ_0037911 are located at chromosome
16and made up 2 exons and 4 exons, respectively (Table 4, Fig. 4).
As shown in Table 1 and Fig. 2A, hsa_circ_0037911 levels in EH
group were significant related to controls group (t ¼ 2.834,
p ¼ 0.005). In Table 2, Fig. 2C and B, we found that hsa_-
circ_0037911 relative fold showed significant differences between
gender (p < 0.0001), smoking (p ¼ 0.001) and drinking (p ¼ 0.049).
However hsa_circ_0002161 have no significant difference in
different state.
3.3. Diagnostic accuracy of hsa_circ_0037911
When adjusted by logistic regression, the model brought four
variable into equation including BMI (OR ¼ 1.132, adjusted
 X. Bao et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6 3

Table 1 p ¼ 0.002),whereashsa_circ_0002161 (AUC ¼ 0.573; p ¼ 0.075) was

The characteristics of demographic and clinical data. not a successful diagnostic marker of EH risk.
Characteristics Non-EH (N ¼ 100) EH (N ¼ 100) c2/t p - value We performed correlation tests betweenhsa_circ_0002161 and
Drinking (Y/N) 20/80 30/70 2.667 0.102
metabolic phenotypes in all participants. Significant correlations
Smoking (Y/N) 16/84 34/66 8.640 0.003 were observed betweenhsa_circ_0037911 and serum creatinine
Sex (F/M) 49/51 49/51 0.000 1.000 (Fig. 3;r ¼ 0.294; p < 0.0001).
Age (years) 61.00 ± 9.26 62.05 ± 9.09 0.867 0.764
BMI (kg/m2) 22.84 ± 2.79 24.27 ± 3.38 3.27 0.001
SBP (mmHg) 129.07 ± 15.0 142.79 ± 14.89 6.50 < 0.0001
DBP (mmHg) 80.25 ± 9.12 84.76 ± 10.35 3.27 0.001 4. Discussion
ALT (IU/L) 25.98 ± 14.92 28.85 ± 23.63 0.056 0.305
AST (IU/L) 28.16 ± 10.24 27.93 ± 7.63 0.063 0.860 As a relatively large class of noncoding RNAs (ncRNAs), CircRNAs
Scr (mmol/L) 91.31 ± 17.83 85.43 ± 20.77 0.006 0.033 are widely expressed in mammalians [7,15], including human. The
BUN (mmol/L) 5.39 ± 1.19 5.14 ± 1.09 0.288 0.122
BUA (mmol/L) 328.29 ± 76.06 340.96 ± 85.29 1.108 0.269
length of the circRNAs may vary significantly, most of them being
Glu (mmol/L) 5.51 ± 1.08 5.73 ± 1.41 0.140 0.208 longer than 200 nt in length [11]. However, significant differences
WBC 6.10 ± 1.65 6.20 ± 1.49 0.452 0.679 between the circRNAs of possessing highly stable structure and
Lym 34.69 ± 7.48 34.6 ± 7.75 0.620 0.943 linear RNAs [16e18]. CircRNAs are specifically expressed as a stable
Monor 34.69 ± 7.48 34.61 ± 7.75 0.192 0.037
expression in cell/tissue dependent and developmental stages [16].
Neut 57.83 ± 7.92 56.87 ± 8.22 0.463 0.402
HCY (mmol/L) 16.46 ± 6.54 15.79 ± 6.31 0.841 0.462 The importance of circRNAs in regulating gene expression at the
LDL (mmol/L) 3.12 ± 0.73 3.13 ± 0.87 0.136 0.928 transcriptional and post-transcriptional levels was shown in a non-
TC (mmol/L) 5.11 ± 0.83 5.03 ± 0.89 0.331 0.516 cancerous proliferative disease, idiopathic pulmonary fibrosis,
HDL (mmol/L) 1.46 ± 0.36 1.41 ± 0.31 0.705 0.229 ovarian cancer cells [19]. In addition, circRNAs expression is
TG (mmol/L) 1.49 ± 0.76 1.53 ± 0.90 0.617 0.742
implicated in the development of human disease states [20]. Zhu
Hsa_circ_0002161 5.33 ± 2.86 5.70 ± 2.34 0.983 0.327
Hsa_circ_0037911 8.30 ± 1.97 8.95 ± 1.18 2.834 0.005 et al. reported that the expression profile of circRNAs were related
to fur skin function change, through gene ontology analysis and
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure; ALT, alanine aminotransferase; AST, glutamic oxalacetic trans- construction of circRNAemiRNAemRNA network [21]. Qin et al.
aminase; Scr, serum creatinine; BUN, blood urea nitrogen; BUA, blood uric acid; Glu, found that hsa_circ_0001649, as a potential binding site for miR-
blood glucose; WBC, white blood cell; Lym, lymphocyte ratio; Monor, monocyte NAs, may act in tumorigenesis and metastasis of hepatocellular
ratio; Neut, neutrophil ratio; HCY, homocysteic acid; LDL, low density lipoprotein; carcinoma [22]. In the cardiovascular field, some heart related
TC, total cholesterol; HDL, high density lipoprotein; TG, triglycerdes; Statistically
significant p - value display in bold.
circRNAs can function as miRNA-223 sponges, which inhibit heart
failure and cardiac hypertrophy [23].The above evidence shows the
great potential of circRNAs in clinical applications and the impor-
p ¼ 0.039); smoking (OR ¼ 6.390, adjusted p ¼ 0.002); Scr
tant role of disease progression, however, studies on circRNAs
(OR ¼ 0.976, adjusted p ¼ 0.038) and hsa_circ_0037911
regulation in cardiovascular diseases are limited, and the value of
(OR ¼ 0.759, adjusted p ¼ 0.026) (Table 3). This multivariate anal-
their clinical diagnosis is still largely unknown.
ysis was uncover the higher level expression of hsa_-
In our study, in order to map the expression of circRNAs in EH, a
circ_0037911can increase the risk of EH, and was not found the any
circRNA microarray was used to select five pairs of whole blood
significant association after adjusting.
sample candidate differential circRNAs for EH and non-EH partici-
In addition, hsa_circ_0037911 was found to be an effective
pants. The microarray analysis of circRNAs identified 209 upregu-
predictor of EH (Fig. 2D; AUC ¼ 0.627;
lated and 78 down regulated circRNAs in the whole blood sample.

Fig. 1. Expression profiles of top 20 circRNAs in blood samples from 5 EH patients compared to age- and sex-matched controls. (A) The heat map picture shows the hierarchical
clustering and differential expression of circRNAs between 5 paired samples. (B) CircRNA-miRNA network maps the interaction relationship between circRNAs and miRNAs.

Please cite this article in press as: X. Bao, et al., A potential risk factor of essential hypertension in case-control study: Circular RNA
hsa_circ_0037911, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.03.059
4 X. Bao et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6

Fig. 2. The differences between (A) EH group and control group, (B)sex, smoking and drinking among EH group, (C)sex, smoking and drinking among control group, (D)the ROC
analysis for hsa_circ_0037911.

Table 2 Table 3
The differential expression level of hsa_circ_0037911 between EH and non-EH. The effect of predictors for EH.

Characteristics Non-EH EH Variable OR (95%CI) Wald p - value

n Mean ± SD p - value n Mean ± SD p - value Sex 0.861 (0.325, 2.279) 0.091 0.762
Age (years) 1.004 (0.964, 1.047) 0.043 0.836
Sex 0.022 < 0.0001
BMI (kg/m2) 1.132 (1.006, 1.274) 4.250 0.039
Male 51 9.21 ± 1.33 51 9.06 ± 1.63
Smoking 6.390 (1.985, 20.576) 9.665 0.002
Female 49 8.67 ± 0.935 49 7.50 ± 2.00
Drinking 0.671 (0.222, 2.031) 0.498 0.480
Age 0.928 0.737
ALT (IU/L) 1.023 (0.993, 1.054) 2.196 0.138
<60 28 8.96 ± 0.83 26 8.41 ± 2.28
AST (IU/L) 0.964 (0.909, 1.023) 1.465 0.226
60 72 8.94 ± 1.30 74 8.26 ± 1.87
Scr (mmol/L) 0.976 (0.954, 0.999) 4.301 0.038
Smoking 0.786 0.001
Glu (mmol/L) 1.168 (0.853, 1.599) 0.938 0.333
Yes 16 8.87 ± 1.53 34 9.19 ± 1.94
BUN (mmol/L) 0.855 (0.631, 1.158) 1.024 0.312
No 84 8.96 ± 1.11 66 7.84 ± 1.84
BUA (mmol/L) 1.003 (0.998, 1.008) 1.270 0.260
Drinking 0.560 0.049
HCY (mmol/L) 0.992 (0.936, 1.052) 0.068 0.387
Yes 20 8.81 ± 1.38 30 8.89 ± 2.03
LDL (mmol/L) 1.455 (0.561, 3.774) 0.595 0.440
No 80 8.98 ± 1.30 70 8.04 ± 1.91
TC (mmol/L) 0.738 (0.293, 1.863) 0.412 0.521
BMI 0.219 0.259
HDL (mmol/L) 0.798 (0.211, 3.021) 0.111 0.739
<24 65 8.84 ± 1.19 52 8.51 ± 1.68
TG (mmol/L) 0.653 (0.373, 1.143) 2.229 0.135
24 35 9.15 ± 1.15 48 8.06 ± 2.24
Hsa_circ_0002161 1.005 (0.884, 1.142) 0.006 0.941
Statistical significant p - values display in bold. Hsa_circ_0037911 0.759 (0.595, 0.967) 4.984 0.026

The top 20 terms of circRNAs network and cluster were shown in
Fig. 1.The results showed that 13 up-regulated circular RNAs(in-
cludinghsa_circ_0037911) regulated hsa-miR-637.Similarly, hsa_-
circ_0037911simultaneously regulated hsa-miR-637, regulated
hsa-miR-2115-5p and regulated hsa-miR-6881-3p. Quantitative
RT-PCR arrays were used during the validation phase.
We first found that hsa_circ_0037911 in the whole blood of EH
were significantly up-regulated than healthy controls (Fig. 2A and
Table 1). Then, we examined the expression level of hsa_-
circ_0037911 from the status of different characteristics of the EH
group and controls group respectively. As shown in Table 2, Fig. 2C
and B, it was also up-regulated in male, smoking and drinking
status among EH group. Moreover, the expression level of hsa_-
circ_0037911 was huge significant difference after adjust by logistic
regression (Table 3). Moreover, we identified for the first time its
potential diagnostic value (Fig. 2D).

Please cite this article in press as: X. Bao, et al., A potential risk factor of essential hypertension in case-control study: Circular RNA
hsa_circ_0037911, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.03.059
 X. Bao et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6
Table 4
The two differently expressed circRNAs in essential hypertension and healthy control.
CircRNA Chrom TxStart TxEnd
Hsa_circ_0002161 16 11988810 11990642
Hsa_circ_0037911 16 11988810 11991892
Fig. 3. The association between Scr and hsa_circ_0037911.
Fig. 4. The pattern of RNA forming in circular.
A recent series of studies have shown that miR-637 acts as a
tumor suppressor is associated with hepatocellular carcinoma,
breast cancer, and follicular thyroid carcinomas [24e26].
Wenboet al. found the up-regulation expression of miRNA-637 and
activity decreased of Akt1 can inhibits migration and invasion of
glioma cell [27]. Conversely, the inhibition of miR-637 expression
and increased Akt1 protein levels correlated with poor progression
and poor prognosis in gliomas [28]. In addition, it has been reported
that miR-637 acts as pressor (e.g. osterix and collagen type IV alpha
1) of gene transcription in post transcriptional [29,30]. MiR-637
also decreases CRP levels by activating the inflammatory pathway
in hypertension [31]. Thus, we have sufficient evidence that hsa_-
circ_0037911 can act as a miR-637 sponge and contribute to the
pathogenesis of EH.
BMI, gender, smoking and drinking were reported as risk factors
for EH [32e35]. Our results also validate this view. Current re-
searches indicated that some clinical data and behavioral data may
associate with hsa_circ_0037911 expression levels. Xuning Wang
et al. found significant association between the expression of
hsa_circ_001988 and the differentiation of colorectal cancer psy-
choneuro immunology (PNI) status [36]. Circular RNA was associ-
ated with cancer stage, size, metastasis and type in cancers
Please cite this article in press as: X. Bao, et al., A potential risk factor of essential hypertension in case-control study: Circular RNA
hsa_circ_0037911, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.03.059
5
Spliced length Best_transcript Gene name Catalog
262 NM_001130007 GSPT1 Exonic
346 NM_001130007 GSPT1 Exonic
[22,37,38]. In our results, we found that the expression levels of
hsa_circ_0037911 and concentration of Scr have a positive corre-
lation. Meanwhile, the relationship between Scr and blood pressure
has reported [39]. Blood pressure can increase with the levels of Scr,
and risk factors for high blood pressure included Scr. We hypoth-
esize that hsa_circ_0037911 may affect blood pressure by changing
the concentration of Scr.
There were reports of the effects of circular RNA in the cardio-
vascular system. The study found that hsa-circ-000595 showed
high expression in hypoxic aortic smooth muscle cells and aortic
aneurysm patients by knockdown of hsa_circ_000595 [40]. Hsa_-
circ_0124644 also can be considered a diagnostic biomarker for
coronary artery disease by combining risk factors and clinical dates
in peripheral blood [41]. Pan et al. speculated circRNAs may pro-
mote the expression of transient receptor potential cation channel
subfamily M member 3 (TRPM3) to become the risk factors of
coronary artery disease [42]. Moreover, it has been demonstrated
that circRNA was risk factor for hypertension by the profiling and
bioinformatics analyses [43].
In conclusion, our study showed that hsa_circ_0037911 signifi-
cantly increased in patients with essential hypertension. Its
expression was closely related to the concentration of scr. Our re-
sults show that hsa_circ_0037911 may play an important role in the
pathogenesis of essential hypertension. It is a potential biomolecule
for clinical prediction and diagnosis.
Conflicts of interest
The authors declared that no competing interests exist.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (Grant No. 81773528); Ningbo Scientific
Innovation Team for Environmental Hazardous Factor Control and
Prevention (Grant No. 2016C51001); Zhejiang Province Social
Development Research Project (Grant No. 2016C33178); K.C. Wong
Magna Fund in Ningbo University, Ningbo Social Development
Research Project (Grant No. 2014C50051); Scientific Research
Foundation Of Graduate School Of Ningbo University.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.bbrc.2018.03.059.
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