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Article
Analysis of the Effects of IL-6 -572 C/G, CRP -757 A/G, and CRP
-717 T/C Gene Polymorphisms; IL-6 Levels; and CRP Levels on
Chronic Periodontitis in Coronary Artery Disease in Indonesia
Sanggap Indra Sitompul 1,2 , Budi Susetyo Pikir 3, *, Aryati 4, *, Citrawati Dyah Kencono Wungu 5 ,
Shafira Kurnia Supandi 6 and Monika Estherlita Sinta 7
1 Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia;
sanggap.in.sitompul-2020@fk.unair.ac.id
2 Medical Staff Group of Cardiology, Doris Sylvanus Hospital, Palangka Raya 73111, Indonesia
3 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga,
Surabaya 60132, Indonesia
4 Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
5 Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga,
Surabaya 60132, Indonesia
6 Medical Staff Group of Oral Health, Doris Sylvanus Hospital, Palangka Raya 73111, Indonesia
7 Department of Periodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
* Correspondence: bsp49@fk.unair.ac.id (B.S.P.); aryati@fk.unair.ac.id (A.)
Abstract: Interleukin 6 (IL-6) and C-Reactive Protein (CRP) play an important role in chronic pe-
riodontitis with coronary artery disease (CAD). Genetic factors can affect a person’s risk of CAD,
which affects one-third of the population. This study investigated the role of IL-6 -572 C/G, CRP -757
A/G, and CRP -717 T/C gene polymorphisms. IL-6 and CRP levels on the severity of periodontitis
in CAD in Indonesia were also evaluated. This case-control study was conducted with mild and
moderate–severe chronic periodontitis groups. A path analysis test was conducted with Smart PLS
with a 95% confidence interval to determine the significant variable for chronic periodontitis. Our
Citation: Sitompul, S.I.; Pikir, B.S.;
study revealed that the effects of IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C gene polymorphisms
Aryati; Wungu, C.D.K.; Supandi, S.K.;
on IL-6 levels and CRP levels were not significant. IL-6 and CRP levels were not significantly dif-
Sinta, M.E. Analysis of the Effects of
ferent between the two groups. We found that IL-6 levels had a significant effect on CRP levels in
IL-6 -572 C/G, CRP -757 A/G, and CRP
periodontitis patients with CAD (path coefficient 0.322, p = 0.003). IL-6 -572 C/G, CRP -757 A/G, and
-717 T/C Gene Polymorphisms; IL-6
Levels; and CRP Levels on Chronic
CRP -717 T/C gene polymorphisms had no effect on the severity of chronic periodontitis in CAD
Periodontitis in Coronary Artery patients in the Indonesian population. We also observed no apparent effects of the influence of gene
Disease in Indonesia. Genes 2023, 14, polymorphisms in IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C genes. Although the IL-6 and
1073. https://doi.org/10.3390/ CRP levels were not significantly different between the two groups, IL-6 levels affected CRP levels in
genes14051073 periodontitis patients with CAD.
Academic Editor: Marina Colombi
Keywords: chronic periodontitis; c-reactive protein; coronary artery disease; gene polymorphism;
Received: 3 April 2023 interleukin-6
Revised: 4 May 2023
Accepted: 9 May 2023
Published: 12 May 2023
1. Introduction
Coronary artery disease (CAD) is a cardiovascular disorder due to atherosclerosis
or atherosclerotic occlusion of the coronary arteries [1]. It is estimated that 17.9 million
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
people died from cardiovascular disease, heart attacks, and strokes in 2019 [2]. Several
This article is an open access article
risk factors contribute to the development of coronary atherosclerosis, including diabetes
distributed under the terms and
mellitus, hypertension, smoking, a diet high in saturated fat, a lack of exercise, inflammatory
conditions of the Creative Commons factors [3], endothelial progenitor cells (EPCs) [4], and chronic periodontitis [5].
Attribution (CC BY) license (https:// Periodontitis is defined as a chronic infectious disease of supporting tissues of teeth.
creativecommons.org/licenses/by/ It is associated with gene variations and environmental interaction [6,7]. This disease is
4.0/). a health problem, especially in developing countries [8]. The prevalence and severity of
periodontitis increase with age, and this disease occurs frequently in males [9,10]. Moreover,
periodontitis is associated with CAD [11,12] and an increase in early mortality [8].
The relationship between periodontitis and cardiovascular disease can develop through
direct and indirect pathways. The direct pathways include bacterial invasion and infection,
and the indirect pathways include increases in C-Reactive protein (CRP) and interleukin-6
(IL-6) [13,14]. Several studies reported that the involvement of CRP and CAD is associ-
ated with periodontitis [15–18]. Additionally, inflammatory mediators are also related to
periodontitis [19,20].
Polymorphisms in the promoter region of the IL-6 gene trigger variations in the tran-
scription [21]. The most frequent polymorphisms occur in 572 C/G and 174 G/C genes. The
two SNPs influencing IL-6 expression and serum levels are associated with periodontitis
susceptibility; however, their geographic and ethnic distribution is distinct [22,23]. The
associations between IL-6 polymorphisms and periodontitis have been extensively studied.
IL-6 -572 may be a genetic risk factor for periodontitis patients in Asian populations, es-
pecially the Chinese population [24]. The IL-6 -174 polymorphism is rare in the Chinese
population [25]. Several studies have also shown a relationship between IL-6 polymor-
phisms and CAD, especially IL-6 -572 C/G [26–28]. Furthermore, a study reported the
polymorphism of IL-6 -572 G/C is correlated with plasma concentrations of IL-6 [29].
CRP gene polymorphisms affect CRP levels in serum. Moreover, about 35–40% of vari-
ations in CRP levels between individuals are inherited [19]. Polymorphisms are associated
with increased plasma CRP levels, -717 A/G, and -757 T/C genes [30]. A significant relation-
ship has been reported between CRP -757 T/C and chronic periodontitis [31]. They play an
important role in the pathophysiology of carotid atherosclerosis [32]. Meanwhile, the CRP
-717 polymorphisms have been shown to be associated with CAD [33] and periodontal
health in Indonesia [34]. Studies about the relationship between IL-6 polymorphisms, CRP
with chronic periodontitis, and CAD are limited, including studies on polymorphisms of
IL-6-572C/G and CRP+1444 C/T [25,35].
To our knowledge, there are no studies on IL-6 -572 C/G, CRP -757 A/G, and CRP -717
T/C gene polymorphisms; IL-6 levels; and CRP levels in chronic periodontitis related to
CAD patients in Indonesia. Therefore, we investigated the roles of IL-6 -572 C/G, CRP -757
A/G, and CRP -717 T/C gene polymorphisms; IL-6 levels; and CRP levels on the occurrence
of chronic periodontitis related to CAD patients.
3. Results
3.1. Subject Characteristics
Our subjects were predominantly male (72.5%) patients who were over <60 years
(83.8%) and had hypertension (78.8%). Our study showed that they did not suffer from
diabetes mellitus (DM) (70%), and the statuses of dyslipidemia, smoking or non-smoking,
and obesity were almost the same in both groups. We found the IL-6 -572 C/G homozygote
minor GG 5 gene polymorphism (6.3%), the CRP -717 T/C homozygote CC 5 gene (6.3%),
and the CRP -757 A/G minor homozygote GG 2 gene (2.5%), as shown in Table 1. The fre-
quencies of the C and G alleles and the A and G alleles appeared similar to the frequencies in
Asian populations (https://www.ncbi.nlm.nih.gov/snp/rs1800796, accessed on 23 Febru-
ary 2023) (https://www.ncbi.nlm.nih.gov /snp/rs3093059, accessed on 23 February 2023).
The frequency of the C allele was higher than the T allele compared to Asian populations
(https://www.ncbi.nlm.nih.gov/snp/rs2794521, accessed on 23 February 2023).
Parameter N Percentage
Male 58 72.5
Gender
Female 22 27.5
<60 years 67 83.8
Age
≥60 years 13 16.3
No 17 21.3
Hypertension
Yes 63 78.8
No 56 70
DM
Yes 24 30
No 42 52.5
Smoking
Yes 38 47.5
No 38 47.5
Dysplidemia
Yes 42 52.5
BMI < 25 kg/m2 44 55
Obesity
BMI ≥ 25 kg/m2 36 45
Mild 40 50
Periodontitis
Moderate–severe 40 50
Genes 2023, 14, 1073 5 of 14
Table 1. Cont.
Parameter N Percentage
CC 40 50
CG 35 43.8
GG 5 6.3
Gene polymorphism in IL-6 572 C/G
Alelles
C 116 72.5
G 44 27.5
TT 42 52.5
TC 33 41.3
CC 5 6.3
Gene polymorphism in CRP 717 T/C
Alelles
T 117 73.1
C 43 26.9
AA 59 73.8
AG 19 23.8
GG 2 2.5
Gene polymorphism in CRP 757 A/G
Alelles
A 137 85.6
G 23 14.4
Range 1.88–57.47
IL-6 levels (pg/L)
Mean ± SD 12.11 ± 10.29
Range 0.3–90
CRP levels (mg/L)
Mean ± SD 8.55 ± 12.70
Range 2.54–6.33
Mean PD
Mean ± SD 4.02 ± 0.62
The frequency distributions of IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C gene
polymorphisms were 0.540, 0.764; 0.099, 0.144; 0.196, 0.907 (x2 , p-value, respectively), ac-
cording to the Hardy–Weinberg equilibrium. We observed no significant difference between
the mild and moderate–severe chronic periodontitis groups. Therefore, the two groups
were considered homogeneous (p > 0.05).
3.2. Polymorphism Analysis of the IL-6 -572 C/G Gene, the CRP -757 A/G Gene, and the CRP -717
T/C Gene for the Severity of Periodontitis, IL-6 Levels, and CRP Levels
Table 2 shows the percentage of genotypes and alleles of the IL-6 -572 C/G gene
polymorphism in patients with moderate–severe periodontitis and mild periodontitis with
CAD. The genotypes and alleles of the two study groups were not statistically different
(p = 0.233).
Regarding the IL-6 -572 C/G gene polymorphism, the percentage of the GG genotype
was higher in the moderate–severe periodontitis group (10%) than in the mild periodontitis
group (2.5%). Our study demonstrated that 5% of the GG genotype was found in the
moderate–severe periodontitis group, while none of the GG genotype was found in the
mild periodontitis group based on the CRP -757 A/G gene. We also found that the percentage
of the CC genotype was lower in the moderate–severe periodontitis group (5%) than in the
mild periodontitis group (7.5%) based on the CRP -717 T/C gene. Genotypes CC, CG, and
GG and alleles C and G in the IL-6 -572 C/G gene; genotypes AA, AG, and GG and alleles A
and G in the CRP -757 A/G gene; and genotypes TT, TC, and CC and alleles T and C in the
CRP -717 T/C gene were not significantly different between the two groups (p > 0.05).
Genes 2023, 14, 1073 6 of 14
Table 2. Relationship between polymorphisms and alleles of the IL-6 -572 C/G, CRP -757 A/G, and
CRP -717 T/C genes with chronic periodontitis.
Chronic Periodontitis
Mild Moderate–Severe ∑ p
N % N %
Gene polymorphism in IL-6 -572 C/G
Genotype 0.233
CC 23 57.5 17 42.5 40
CG 16 40 19 47.5
GG 1 2.5 4 10 35
5
Total 40 100 40 100 80
Alleles 0.111
C 63 78.8 53 66.2 11
G 17 21.2 27 33.8 6
44
Total 80 100 80 100 16
0
Gene polymorphism in CRP -757 A/G
Genotype 0.332
AA 31 77.5 28 70 59
AG 9 22.5 10 25 19
GG 0 0 2 5 2
Total 40 100 40 100 80
Alleles 0.368
A 71 88.8 66 82.5 13
G 9 11.2 14 17.5 7
23
Total 80 100 80 100 16
0
Gene polymorphism in CRP -717 T/C
Genotype 0.653
TT 19 47.5 23 57.5 42
TC 18 45 15 37.5 33
CC 3 7.5 2 5 5
Total 40 100 40 100 80
Alleles 0.476
T 56 70 61 76.2 11
C 24 30 19 23.8 7
43
Total 80 100 80 100 16
0
Table 3 shows the polymorphism of the IL-6 -572 C/G gene. We found that the average
IL-6 level was higher in the GG genotype than in the CC and CG genotypes; however, it
was not statistically significant (p = 0.579). The CRP -757 A/G gene polymorphism showed
a lower average HsCRP level in the GG genotype compared to the AA and AG genotypes.
However, it was not significantly different (p = 0.842). The average HsCRP level was lower
in the CC genotype (4.580 mg/L) compared to the TT and TC genotypes (8.002 mg/L;
9.842 mg/L); however, there was no apparent significant difference (p = 0.490).
in the CC genotype (4.580 mg/L) compared to the TT and TC genotypes (8.002 mg/L; 9.842
mg/L); however, there was no apparent significant difference (p = 0.490).
Genes 2023, 14, 1073 7 of 14
Table 3. Relationship between IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C gene polymorphisms;
IL-6 levels; and CRP levels in periodontitis and CAD.
N IL-6 -572
3. Relationship between
TableGenotype MeanC/G, CRP -757 A/G, and CRP -717Standard
Min-Max T/C gene polymorphisms;
p-Value
IL-6 levels; and CRP levels in periodontitis and CAD. Deviation
IL-6 gene polymorphism -572 C/G on IL-6 levels (pg/L)
CC Standard
Genotype N 40 12.448
Mean (1.88–45.13)
Min-Max 9.419 p-Value
Deviation
CG 35 11.131 (2.33–57.47) 10.869 0.579
GG IL-6 gene
5 polymorphism
16.314 C/G on IL-6 levels (pg/L)
-572(3.91–31.80) 13.768
CC 40 12.448 (1.88–45.13) 9.419
CRP gene polymorphism -757 A/G on CRP levels (mg/L)
CG 35 11.131 (2.33–57.47) 10.869 0.579
AA
GG 5 59 9.231
16.314 0.3–90
(3.91–31.80) 13.986
13.768
AG 19 6.984 0.9–33.6
CRP gene polymorphism -757 A/G on CRP levels (mg/L) 8.401 0.842
AA
GG 59 2 9.231
3.250 0.3–90
2.7–3.8 13.986
0.778
AG 19 6.984
CRP gene polymorphism -717 T/C0.9–33.6 8.401
on CRP levels (mg/L) 0.842
GG 2 3.250 2.7–3.8 0.778
TT 42 polymorphism
CRP gene 8.002 0.3–90
-717 T/C 14.808
on CRP levels (mg/L)
TTTC 42 33 9.842
8.002 0.5–39.8
0.3–90 10.482
14.808 0.490
TCCC 33 5 9.842
4.580 0.5–39.8
0.5–11.4 10.482
4.906 0.490
CC 5 4.580 0.5–11.4 4.906
3.3. Correlation between IL-6 Levels, CRP Levels, and the Severity of Periodontitis in CAD
3.3.IL-6
Correlation between
and HsCRP IL-6 Levels,
levels CRP Levels,
were higher in theand the Severity of Periodontitis
moderate–severe in CAD
chronic periodontitis
group IL-6
thanand HsCRP
in the mild levels were higher
periodontitis in the
group. Ourmoderate–severe
results showed chronic
that theperiodontitis
IL-6 levels ingroup
the
thanand
mild in the mild periodontitis
moderate–severe group. Our
periodontitis resultswere
groups showed that±the
11.245 SDIL-6 levels
8.646 andin12.982
the mild
±
and moderate–severe
11.752, periodontitis
respectively. Moreover, the CRPgroups were
levels in the mild±periodontitis
11.245 SD 8.646 andand 12.982 ± 11.752,
moderate–
respectively.
severe Moreover,
periodontitis groupsthe CRP
were levels
7.675 ± SD in9.143
the mild periodontitis
and 9.420 ± 15.548, and moderate–severe
respectively (Figure
periodontitis
1). groups were 7.675 ± SD 9.143 and 9.420 ± 15.548, respectively (Figure 1).
Figure
Figure 1. 1. Comparison
Comparison analysis
analysis of of IL-6
IL-6 andand HsCRP
HsCRP levels
levels in periodontitis
in periodontitis patients
patients with
with CAD.
CAD. TheThe
* *
sign
sign indicates
indicates the
the sample
sample data
data number,which
number, whichisisananextreme
extremeoutlier.
outlier.
3.4.
3.4. Path
Path Analysis
Analysis Effects
Effects of of IL-6
IL-6 -572
-572 C/G,
C/G, CRP
CRP -757
-757 A/G,
A/G, and
and CRP
CRP -717
-717 T/C
T/C Gene
Gene
Polymorphisms; IL-6 Levels; and CRP Levels on Chronic Periodontitis in CAD
Polymorphisms; IL-6 Levels; and CRP Levels on Chronic Periodontitis in CAD
IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C gene polymorphisms; IL-6 levels; and
IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C gene polymorphisms; IL-6 levels; and
CRP levels had no apparent effects on the severity of chronic periodontitis in CAD based
CRP levels had no apparent effects on the severity of chronic periodontitis in CAD based
on the path analysis (Figure 2 and Table 4). Our results also demonstrated that CRP -757
onA/G,
the path analysis
CRP-717 T/C, (Figure
and IL-6 2 and
-572 Table 4). Our
C/G gene results also demonstrated
polymorphisms had no effectthat
on CRP
IL-6 -757
levels
A/G, CRP-717 T/C, and IL-6 -572 C/G gene polymorphisms had no effect on IL-6
(p > 0.05). Interestingly, IL-6 levels affected CRP levels in periodontitis patients withlevelsCAD
(p
> (path
0.05). coefficient
Interestingly, IL-6 levels
0.322, p = 0.003). affected CRP levels in periodontitis patients with CAD
(path coefficient 0.322, p = 0.003).
Genes 2023,
Genes 2023, 14,
14, 1073
x FOR PEER REVIEW 88of
of 14
14
Figure 2.
Figure 2. Path
PathAnalysis
AnalysisEffects
Effectsofof IL-6
IL-6 -572
-572 C/G,
C/G, CRPCRP
-757-757
A/G,A/G, and -717
and CRP CRPT/C
-717gene
T/Cpolymorphisms;
gene polymor-
phisms; IL-6 levels; and CRP levels on chronic periodontitis
IL-6 levels; and CRP levels on chronic periodontitis in CAD. in CAD.
histories of CAD [45]. A recent study showed a relationship between the IL-6 -572 C/G poly-
morphism and CAD. The CG and GG genotypes increase the risk of periodontitis-related
CAD [25]. Gene polymorphisms in IL-6 influence IL-6 expression and cause. variations
in transcription and expression between individuals [46,47]. The increase in IL-6 levels
can be influenced by the IL-6 -572 gene polymorphism [29], idiopathic pulmonary arterial
hypertension [48], DVT [49], and the interaction of the IL-6 gene promoter haplotype [45].
No studies have focused on the CRP -757 A/G and CRP -717 T/C gene polymorphisms
for chronic periodontitis in CAD. Our study showed no significant difference in the. pro-
portions of the AA, AG, and GG genotypes or the A and G alleles (-757 A/G). We did not
observe significant differences in the proportions of the genotypes TT, TC, CC, T, and C
(-717 T/C) and the CRP levels in both groups. The highest mean CRP levels were in the AA
genotype in the CRP -757 gene and the TC genotype in the CRP -717 gene, but they were
not statistically significant. Similar studies also reported a significant association of CRP
-757 T/C with chronic periodontitis in South India and high-risk TT genotypes [30]. The C
allele is associated with increased CRP levels [33,50]. However, other studies have found
an interaction effect between gender and obesity on increasing HsCRP [51]. This condition
reinforces the genetic influence on CRP production [52].
The CRP-717 T/C gene is not related to periodontitis [31,53] including in the Indonesian
population [54]. It provides a complementary indicator of periodontitis risk [33]. Another
study reported that the CRP -717 polymorphism predisposes to CAD allele A [32]. A
relationship was also reported between CRP gene polymorphisms and increased CRP
lebels in several populations, including -717 and -757 [29]. Our study reveals no effects
of polymorphism on the severity of periodontitis in CAD patients. The results might
have been affected by the sample size, the interaction of environmental and confounding
factors [55], the differences in allele and genotype frequencies, and the heterogeneity of
genetic susceptibility in several ethnic groups and races [49,56].
In the present study, the frequency of the G allele at IL-6 -572 was lower than in the
Asian population. In contrast, its frequency in the European population reached 95% [57].
Allele G at CRP -757 showed a frequency of 14.4%, which is lower than the frequencies in
Asia (16%) and the European population (6%) [58]. The frequency of the C allele in CRP
-717 is 26.9% higher than in the Asian population (16%) and in Europe (28%) [59]. A study
reported that -717 C/T dominant C allele with homozygote recessive in Iranian population
with chronic periodontitis [60]. Periodontitis was found in -717 dominant genotypes AA
(46.1%), AG (43%), GG (10.7%), 757 TT (81.5%) TC (16.9%), and CC (1.5%) in the South
Indian population [25]. The IL-6 and CRP gene polymorphisms might be influenced by IL-6
and CRP levels, especially in terms of the sample size, the limited number of polymorphism
loci, and the multifactorial influences regulating these inflammatory mediators.
and bone resorption [73,74]. These conditions trigger the loss of the periodontal ligament
and alveolar bone [41]. Furthermore, RANKL or OPG has a potential marker of alveolar
bone damage [75–77].
IL-6 and CRP play important roles in forming CAD plaques [17,26,78–80]. CRP is a
major parameter for treating CAD patients with periodontitis [17,81,82]. In contrast, CRP
is not associated with periodontitis and CAD risk [49,58,83,84]. Another study showed the
presence of CRP and IL-6 in periodontitis patients with CAD [85].
The results of the current study showed that the CAD with moderate–severe peri-
odontitis group presented a higher level of IL-6 and CRP in comparison with the mild
periodontitis group; however, our results were not statistically significant. This difference
could be due to differences in examination methods, especially the probing depth limit [86],
the involvement of Acute Myocardial Infarction [87], and the use of statins in CHD pa-
tients to reduce levels of inflammatory mediators [88]. In addition, IL-6 and CRP can be
influenced by psychosocial or environmental pressure [89].
This study is the first study to analyze the effects of IL-6 -572 C/G, CRP -757 A/G,
and CRP -717 T/C gene polymorphisms; IL-6 levels; and CRP levels on the severity of
periodontitis in CAD, especially in the Indonesian population. However, there are several
limitations. First, the sample size was only obtained from one center. Second, the type of
polymorphisms studied were limited to the IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C
genes. Third, our study focused on the severity of chronic periodontitis in CAD and did
not involve a normal group (without periodontitis). Further studies are needed to involve
healthy controls and more centers.
5. Conclusions
The chronic periodontitis population with CAD had the majority of CC, AA, and TT
genotypes in IL-6 -572 C/G, CRP -757 A/G, and CRP -717 T/C C/G gene polymorphisms.
Polymorphisms were not affected by the severity of chronic periodontitis, IL-6 levels, and
CRP levels. In addition, IL-6 levels affected CRP levels in moderate–severe periodontitis
patients with CAD. Further studies are warranted to involve IL-6 and CRP polymorphisms
at other loci and with larger samples.
Author Contributions: Conceptualization: S.I.S., B.S.P. and A.; methodology: S.I.S., S.K.S., B.S.P. and
A.; sample collection: M.E.S. and S.I.S.; formal analysis: S.I.S. and M.E.S.; writing—original draft
preparation: S.I.S. and C.D.K.W.; writing—review and editing: C.D.K.W. and A.; supervision: B.S.P.
and A. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the Institutional Ethics Committee of dr. Doris Sylvanus Hospital
(ethical clearance number 5641/UM-TU/RSUD/11-2021).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: All relevant data are within the paper.
Acknowledgments: The authors thank Yusuf Galenta, Andreriyanto, Nia Aprilia Holli, Ripka Br
Tarigan, Rina Triana, Winih Ayu Jati who kindly helped in this study. We also sincerely thank to all
participant in this study.
Conflicts of Interest: The authors declare no conflict of interest.
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