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Association of gene polymorphisms with women urinary incontinence

  • Povilas Aniulis EMAIL logo , Aurelija Podlipskyte , Alina Smalinskiene , Rosita Aniuliene and Mindaugas Jievaltas
Published/Copyright: August 25, 2021
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Open Medicine
From the journal Open Medicine Volume 16 Issue 1

Abstract

Aim of study was set to investigate the association of women urinary incontinence (UI) with serotonin receptor HTR2A T102C and beta 3-adrenergic receptor ADRB3 Trp64Arg genes polymorphisms. The study included 110 women with Urge, Stress, and Mixed UI types and the control group – 105 continent women. Both groups have filled in the ICIQ-FLUTS questionnaire and their blood genotyping was performed. Urge UI subgroup was older and had higher body mass index (BMI) in comparison to other UI types and control group. More than half of all women had family history of UI in Stress UI and Mixed UI subgroups. The frequency of HTR2A T102C gene polymorphism’s minor allele C and genotype CC was significantly more expressed in Urge UI subgroup, as compared with control group (C-77.3 vs 58.7%, p = 0.007 and CC-57.6 vs 31.1%, p = 0.015). The ADRB3 Trp64Arg gene polymorphism did not differ between groups. The regression analysis revealed CC genotype (OR = 3.06, 95% CI: 1.11–8.43; p = 0.030) and allele C (OR = 2.53, 95% CI: 1.16–5.53; p = 0.020) were risk factors for development of Urge UI. We conclude that HTR2A T102C gene polymorphism affected the development of Urge UI.

Keywords: ADRB3; HTR2A; serotonin receptor 2A; gene polymorphism; UI

1 Introduction

Urinary incontinence (UI) is the involuntary flow of urine due to a disruption of the normal urination mechanism, causing medical, social, and hygienic problems. For a woman suffering from this disease, the quality of life deteriorates very sharply [1,2]. The most common types of UI in women, according to consensus definitions developed by the International Urogynecological Association/International Continence Society, include stress urinary incontinence (SUI), mixed urinary incontinence (MUI), and urge urinary incontinence (UUI) [3]. UUI is a major symptom in the diagnosis of overactive bladder syndrome (OAB) [4].

Age is probably the best-known risk factor in the etiology of UI and the incidence of UI correlates directly with age. Approximately every 5–6th of 30-year-old female patients, about every second 50-year-old female patients, and around 80% of elderly women of 80 years old suffer from at least one type of UI [5,6,7]. A number of risk factors, such as lower estrogen levels in the vagina, bladder, and urethra during menopause, BMI > 30 kg/m2 [8], number of pregnancies [9,10], obstetrical events, at least one vaginal birth (much higher risk than delivery by cesarean) [11,12], frequent use of caffeine, smoking [13], and constipation [14], and neurological diseases such as stroke, multiple sclerosis, or Parkinson’s disease [15] are known as significant for the development of different types of UI.

It is known that family history of UI could be a risk factor for development of UI in women. The results from population-based Norwegian EPICONT study showed 1.3-fold greater risk for UI if mother had UI and 1.6-fold risk if an older sister had UI [16].

Ethnicity is also considered as one of the risk factors for UI. African-Americans are more likely to suffer from UUI (45.9%) than white (43.4%), hispanic (42%), and Asian-born women (26.6%) [13]. Heritability of 34–41% for UI was determined in monozygotic and dizygotic twin studies [17,18].

These findings support the hypothesis about genetic basis toward developing of UI.

There are some clinical studies that reported associations among female with UI and genetic factors, particularly in single-nucleotide polymorphism (SNP) [19,20].

Researchers Penney et al. evaluated 6120 women and found that 68 SNP, located in 2 loci, chromosomes 8q23.3 and 1p32.2, were significantly associated with UI [21].

However, the evidence on SNPs in UI is still scarce. It is known that urinary function is controlled by the central and peripheral nervous systems through various neurotransmitters [15].

The SNP of the beta 3-adrenoceptor (ADRB3) Trp64Arg gene polymorphism or rs4994 is a mutation of the thymine at position 190 to cytosine and changes protein receptor in 64th position of tryptophan to arginine [22]. The SNP (rs4994) of ADRB3 gene has been extensively studied in obesity, type-2 diabetes, and other diseases pathogenesis and found that ADRB3 expression in bladder cells has been shown to be very high and promotes muscle relaxation [20].

In the human bladder, the detrusor muscle is mainly released through the activation of ADRB3 [23,24]. Recent studies suggest that activation of ADRB3 in urothelium and bladder detrusor muscle may have an inhibitory effect on afferent bladder activity, suggesting that ADRB3 affects bladder sensitivity [25,26].

It is also thought that SNP of the ADRB3 gene may lead to incomplete detrusor relaxation during the bladder filling phase. As a result, it is thought that this polymorphism may contribute to the development of UUI.

Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine transmitter that is primarily found in the gastrointestinal tract, platelets, and brain. 5-HT causes smooth muscle contraction in various tissues such as the intestine, arteries, and bladder [27].

The serotonin 2A receptor gene (HTR2A) is located on 13 chromosome (13q14-21) and consists of three exons spanning >20 kb.

For these reasons, we hypothesized that SNP in these two genes may have a significant association with bladder function and the development of UI. Identification of genetic factors, associated with UI, could result to a better understanding of etiologic pathways and would allow planning the new treatment strategies.

The aim of our study is to investigate the association of women UI with serotonin receptor (HTR2A) T102C and beta 3-adrenergic receptor (ADRB3) Trp64Arg genes polymorphisms as a risk factor for the development of different types of UI.

2 Materials and methods

2.1 Ethics

The study protocol was approved by Biomedical Research Ethics Committee of Lithuanian University of Health Sciences (LUHS) (permission No. BE-2-50).

2.2 Study population and setting

This case control study included women from 40 to 70 years old, consecutively admitted for consultation to gynecology or urology outpatient departments at the Hospital of LUHS. Duration of the study was 24 months. All participants signed informed consent to participate in the study.

The exclusion criteria were more than two births, oncological history, diabetes mellitus, previous pelvic surgery, previous treatment of UI, persistent urinary tract infection, neurological diseases that can cause UI, history of mental disorders, and BMI higher than 35 m2/kg.

Sociodemographic and medical history were collected and International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) was filled in for evaluating female lower urinary tract symptoms [28]. Study subjects were classified to control group (continent women) and study group – subjects with different types of UI (SUI, UUI, and MUI). Women reporting no clinically significant symptoms of UI of any type (overall score ≤2 on ICIQ-FLUTS) were included into control group [29]. The final diagnosis of type of UI medical examination of gynecologist and urologist was performed – the ultrasound to evaluate residual urine, cough, and valsalva tests. In the cases of MUI, urodynamic evaluation (uroflowmetry and cystometry) was performed. Thus, all incontinent women were divided into three subgroups according to diagnostic criteria for different types of UI: SUI, wet and dry types of UUI, and MUI.

From 260 women, invited to participate in the study, 10 declined to participate, 22 had exclusion criteria, and three returned incomplete questionnaires. Ten genotyping was not performed due to sample contamination.

The final study sample consisted of 110 women (mean age 57.0 (9.3)), diagnosed with three types of UI, and 105 women (mean age 52.4 (8.2)) as healthy control group.

Total response rate was 82.7%. The venous blood was taken from all study participants and genotyping of ADRB3 and HTR2A gene polymorphism was performed.

3 Assessments

3.1 The ICIQ-FLUTS questionnaire

ICIQ-FLUTS questionnaire consists of three subscales (12 questions) and it is completed in average of 4–5 min. All answers are based on experiences with LUTS in the previous four weeks. Each element of the question has two sections. The first section asks about the symptom and quantifies it on a Likert scale (0 – never to 4 – always). The second section identifies the extent to which this symptom bothers and disturbs subject (the score is calculated by domains and it ranges from 0 – there are no problems, to 10 – it is very troublesome).

The first subscale of the ICIQ-FLUTS is for the symptoms of bladder filling (four questions, sum of the scores from 0 to 16), the second – for the symptoms of voiding (three questions, sum is from 0 to 12), and the third – for the symptoms of incontinence (five questions, score is from 0 to 20). Higher scores indicate stronger symptoms. The different bladder filling, voiding, and incontinence scores represent different types of UI. In this study, we used the ICIQ-FLUTS, validated for use in Lithuanian language according to the author’s recommendations [30].

3.2 ADRB3 and HTR2A genotyping

Genotyping of the ADRB3 rs4994 and HTR2A rs6313 was done at the Laboratory of Genetics of the Institute of Biology Systems and Genetic Research of LUHS. Blood samples of DNA extraction were collected in ethylenediaminetetraacetic acid (EDTA) tubes. Genomic DNA from peripheral blood leucocytes was extracted using genomic DNA purification kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s recommendations. Single-nucleotide polymorphisms (SNPs in ADRB3 gene (rs4994)) were estimated by using a commercially available genotyping kit C_2215549_20 and in HTR2A gene (rs6313) C_3042197_1_ (Applied Biosystems, Foster City, CA, USA). The Applied Biosystems 7900HT Real-Time Polymerase Chain Reaction System (Applied Biosystems, Foster City, CA, USA) was used for SNPs detection. The cycling program started with heating at 95°C for 10 min, followed by 40 cycles (at 95°C for 15 s and at 60°C for 1 min). Finally, allelic discrimination was done by using SDS 2.3 software provided by Applied Biosystems.

3.3 Statistical analysis

The clinical characteristics were reported by frequencies and percentages for the categorical variables and with means and standard deviations for the continuous variables. A χ 2 test is used to calculate the Hardy-Weinberg equilibrium (HWE), complied with the law of equilibrium (p > 0.05). Numeric data means were compared with the use of the parametric ANOVA test or nonparametric Kruskal–Wallis K tests. The four inheritance models (codominant, dominant, recessive, and over dominant) were applied in a logistic regression analysis to estimate the risk of UI between cases in UI subgroups and control group. Odds ratio (OR) with a 95% confidence interval (CI) was reported for allelic comparisons and genotype frequencies between the different UI type of subgroups and the control group. Logistic regression analysis was adjusted by age, family history for UI, and BMI. Statistical analyses were performed with the Statistical Package for the Science Software v.22 (SPSS, Chicago, IL). The level of significance was set at p < 0.05.

4 Results

The comparison of sociodemographic and clinical characteristics collected from medical history and ICIQ-FLUTS questionnaire was presented in Table 1.

Table 1

The comparison of sociodemographic and clinical data among women with UI and control group

Characteristics Control group, n = 105 Women with UI (subgroups), n = 110 p value
SUI, n = 55 UUI, n = 34 MUI, n = 21
Age (years), mean ± SD 52.4 ± 8.2 53.0 ± 9.2 61.8 ± 7.3 59.6 ± 8.3 <0.001
10.676
2<0.001
3 0.001
BMI (kg/m2), mean ± SD 24.6 ± 4.0 26.0 ± 3.3 27.4 ± 4.0 25.6 ± 3.1 0.001
1 0.026
2 0.001
30.268
Family history for UI, n (%) 7 (6.7) 28 (50.9) 10 (29.4) 11 (52.4) <0.001
1 <0.001
2 0.001
3 <0.001
ICIQ-FLUTS, median (IQR) 1.0 (0.0–2.0) 11.0 (8.0–14.0) 19.0 (14.8–21.3) 23.0 (17.0–26.0) <0.001 #
1 <0.001
2<0.001
3 <0.001
Filling (score) 1.0 (0.0–2.0) 1.0 (0.0–3.0) 10.0 (8.0–11.0) 9.0 (5.5–10.0) <0.001 #
1 0.007
2<0.001
3 <0.001
Voiding (score) 0.0 (0.0–0.0) 1.0 (0.0–2.0) 0.0 (0.0–1.0) 1.0 (0.0–2.0) <0.001 #
1 <0.001
2<0.001
3 <0.001
Incontinence (score) 0.0 (0.0–0.0) 8.0 (7.0–10.0) 8.0 (5.0–11.0) 13.0 (11.0–15.0) <0.001 #
1 <0.001
2<0.001
3 <0.001

Difference between control group and different UI subgroups was evaluated by χ 2 and one-way ANOVA or nonparametric Kruskal–Wallis test#.

p 1 Control group vs SUI, p 2 Control vs UUI, p 3 Control vs MUI.

Abbreviations: UI, urinary incontinence; SUI, stress urinary incontinence; UUI, overactive bladder; MUI, mixed urinary incontinence; BMI, body mass index; ICIQ-FLUTS, international consultation on incontinence modular questionnaire female lower urinary tract symptoms; SD, standard deviations; IQR, interquartile range (P25–P75).

In bold, p < 0.05.

Age and BMI were significantly higher in UUI subgroup, as compared to SUI, MUI subgroups, and study control group. There were more than half of women with family history of UI in SUI and MUI subgroups. In UUI subgroup, family history of UI was significantly lower than that in SUI and in MUI subgroups (29.4 vs 50.9%, respectively; p = 0.049 and 52.4%, respectively, p = 0.094), but significantly higher than that in control group (6.7%; p < 0.001).

The total score of the ICIQ-FLUTS questionnaire, reported higher severity of LUTS symptoms, was statistically significantly higher in UUI and MUI subgroups in comparison to SUI subgroup and healthy control group. The filling scores in UUI and MUI subgroups were significantly higher than SUI (p < 0.001); however, SUI did not differ from control group. The voiding score was significantly higher in all women with UI (p < 0.001), without significant differences among study subgroups. The incontinence score was significantly higher in MUI in comparison to other subgroups (p < 0.05) and control group; the severity of incontinence did not differ among SUI and UUI subgroups.

Allele frequencies and genotype distribution between the control group and SUI, UUI, and MUI subgroups are presented in Table 2. The frequency of HTR2A (rs6313) T102C gene polymorphism’s minor allele (C) was significantly more expressed in the UUI subgroup, as compared with control group (77.3 vs 58.7%, respectively, p = 0.007). The polymorphism of HTR2A genotype CC was statistically significantly more expressed in UUI subgroup patients, as compared with control group (57.6 vs 31.1%, respectively, p = 0.015); without differences in other UI subgroups. The allele frequencies and genotype distribution of ADRB3 (rs4994) Trp64Arg gene polymorphisms did not differ statistically between the UI subgroups and study control group.

Table 2

Allele frequencies and genotype distribution among the control group (n = 105) and women with different types of UI (subgroups): SUI (n = 55), UUI (n = 34) and MUI (n = 21)

Polymorphism Genotype/allele Control group, n (%) SUI, n (%) UUI, n (%) MUI, n (%) p value
HTR2A (rs6313) C > T Genotype 0.037
  CC 32 (31.1) 26 (49.1) 19 (57.6) 7 (33.3) 10.073
  CT 57 (55.3) 20 (37.7) 13 (39.4) 9 (42.9) 2 0.015
  TT 14 (13.6) 7 (13.2) 1 (3.0) 5 (23.8) 30.422
Allele 0.021
  C 121 (58.7) 72 (67.9) 51 (77.3) 23 (54.8) 10.115
  T 85 (41.3) 34 (32.1) 15 (22.7) 19 (45.2) 2 0.007
30.635
ADRB3 (rs4994) T > C Genotype 0.693
  CC 1 (1.0) 0 (0.0) 1 (2.9) 1 (4.8) 10.755
  TC 14 (13.3) 8 (14.5) 3 (8.8) 3 (14.3) 20.562
  TT 90 (85.7) 47 (85.5) 30 (88.8) 17 (81.0) 30.436
Allele 0.810
  C 16 (8.1) 8 (7.3) 5 (7.4) 5 (11.9) 10.911
  T 194 (91.9) 102 (92.7) 63 (92.6) 37 (88.1) 20.943
30.360

p 1 Control group vs SUI, p 2 Control group vs UUI, p 3 Control group vs MUI.

Abbreviations: UI, urinary incontinence; SUI, stress urinary incontinence; UUI, overactive bladder; MUI, mixed urinary incontinence.

In bold, p < 0.05.

The logistic regression analysis was performed to evaluate polymorphism as the risk factor for three types of UI (Table 3), considering the fact that SUI, UUI, and MUI subgroups and control group were not homogeneous (according to age, BMI, and family history of UI).

Table 3

ADRB3 Trp 64 Arg and HTR2A T102C polymorphisms influence in different UI types

Polymorphism Model Genotype Control vs SUI, OR (95% CI) p-value Control vs UUI, OR (95% CI) p-value Control vs MUI, OR (95% CI) p-value
HTR2A (rs6313) C > T Allele T 1 0.226 1 0.020 1 0.351
C 1.43 (0.80–2.56) 2.53 (1.16–5.53) 0.66 (0.28–1.57)
Dominant CT + TT 1 0.063 1 0.030 1 0.688
CC 2.2 (0.96–4.94) 3.06 (1.11–8.43) 0.77 (0.21–2.81)
Recessive TT 1 0.640 — — 1 0.228
CT + CC 1.03 (0.92–1.14) 2.51 (0.56–11.24)
Codominant CC 1 1 1
CT 0.38 (0.15–0.93) 0.034 0.39 (0.14–1.12) 0.081 0.95 (0.21–4.30) 0.949
TT 0.81 (0.43–1.52) 0.519 — — 1.31 (0.58–2.97) 0.523
Over dominant 1 0.055 1 0.239 1 0.599
0.45 (0.20–1.02) 0.56 (0.21–1.48) 0.73 (0.22–2.40)
ADRB3 (rs4994) T > C Allele C 1 0.524 1 0.936 1 0.284
T 1.41 (0.49–4.04) 0.95 (0.25–3.65) 0.49 (0.13–1.80)
Dominant TT 1 0.793 1 0.974 1 0.378
TC + CC 0.86 (0.29–2.58) 0.98 (0.21–4.54) 1.98 (0.44–8.98)
Recessive TT + CC — — —
CC
Codominant TT 1 0.941 1 0.875 1 0.545
TC 1.04 (0.35–3.13) 0.88 (0.17–4.59) 1.67 (0.32–8.87)
CC — — —
Over dominant TT + CC 1 0.875 1 0.870 1 0.559
TC 1.09 (0.37–3.22) 0.87 (0.17–4.58) 1.63 (0.32–8.27)

Age, family history for UI and BMI were introduced in the model as control variables.

Abbreviations: UI, urinary incontinence; SUI, stress urinary incontinence; UUI, overactive bladder; MUI, mixed urinary incontinence, OR, odd ratio.

In bold, p < 0.05.

The dominant model revealed CC genotype 3-fold increased risk for the development of the UUI (OR = 3.06, 95% CI: 1.11–8.43; p = 0.030). 2.5-fold increased risk of the development of UUI was found for every copy of allele C (OR = 2.53, 95% CI: 1.16–5.53; p = 0.020).

The codominant model revealed that CT genotype was an independent variable, decreasing risk for the development of SUI (OR = 0.38, 95% CI: 0.15–0.93; p = 0.034).

5 Discussion

Polymorphism of the HTR2A gene T102C (rs6313) is associated with the CNS serotonin metabolism system, which modulates bladder activity function [18]. In rats with partial bladder outflow obstruction, HTR2A receptors mRNA levels were increased in detrusor and subserosal layer of the bladder, but not in the urothelium. The increase in HTR2A receptor mRNA persisted from 3 to 14 days after induced obstruction. These results indicated that the induced partial urinary outflow obstruction caused an increase in the HTR2A receptor in the detrusor and subserosal layer of the bladder, which was later likely to result in forced bladder contraction [31].

We have found statistically significant difference in family history of UI between three evaluated types of UI and control group. This supports our hypothesis that UI may be related to genetic factors. The study of Ferreira et al. in 2011 has found that a family history of OAB is an independent risk factor for UUI and OAB syndrome [32]. However, our study showed opposite results: family history for UI was statistically significantly lower in the UUI subgroup compared with SUI and MUI subgroups. To explain the reason of that, our study result is controversial.

The next finding in our study is the association between HTR2A gene T102C polymorphism and development of UUI. It is known that the relation between HTR2A gene polymorphism and UI was evaluated in Brazilian study and has found the significant correlation between TT genotype and UI: subjects with the TT genotype had a 2-fold greater risk for UI than subjects with other genotypes [20]. Noronha et al.’s study has reported similar association between the TT genotype versus CC + CT genotypes and UI (OR = 2.69; 95% CI: 1.37–5.29; p = 0.013). And study group participants with the TT genotype were more prone to UUI, but participants with CC and TC genotype for SUI [33].

Our study demonstrated that the association of HTR2A gene (rs6313) T102C polymorphism’s minor allele (C) was statistically significantly more common in the UUI subgroup compared to control group and dominant model showed that CC genotype has 3-fold higher risk for the development of an UUI; 2.5-fold increase of risk of the development of UUI was found for every copy of allele C. These results appear to be in contrast to the aforementioned studies, perhaps this was due to the fact that women with fewer risk factors were included in our study.

Our study did not show significant associations between ADBR3 gene Trp64Arg polymorphism and any type of UI; however, other studies showed different results.

ADBR3 gene polymorphisms and UI were evaluated in the study of Honda et al. They included 100 women with UUI and OAB and 101 of healthy control group; DNA from hair root samples were obtained for ADRB3 gene analysis. This study showed that overall frequency of the 64Arg variant (heterozygous plus homozygous) in patients with UUI was 47% and significantly higher than the frequency of 22.8% found in control group. The authors concluded that the Trp64Arg polymorphism in the ADBR3 gene is weakly but significantly associated with UUI and OAB syndrome [34]. In the Brazilian study, scientists have investigated genetic polymorphisms in women with UUI and OAB syndrome. There were digested homozygous T allele 69.75%, heterozygotes 29.8%, and homozygous A allele 0.45%. A comparison between the groups showed higher prevalence of the digested homozygous T allele genotype in women with UUI and OAB syndrome. Family history of OAB syndrome was evaluated as an independent risk factor for UUI and OAB syndrome. This study concluded that the Trp64Arg polymorphism was associated with UUI and OAB syndrome in the Brazilian population [32]. These two studies were included in meta-analysis done by Cartwright et al. (2015), which concluded that the Trp64Arg (rs4994) polymorphism of the ADRB3 gene was associated with UUI and OAB (OR = 2.5; 95% CI: 1.67–3.60; n = 419), with no heterogenity [19].

Despite the fact that we did not obtain statistically significant findings in the ADRB3 gene polymorphism in different types of UI, an assessment of previous research findings, as well as strong association with a family history in UUI and OAB, we could suggest that UI has a genetic impact. The limitation of our study is the relatively small sample size to make the strong conclusion about significant genetic associations.

The strength of our study is the strict selection of the study sample, medical examination, and use of ICIQ-FLUTS questionnaire for clinically approved diagnosis of three types of UI. To our knowledge, this is the first study evaluated that concluded that the HTR2A gene T102C polymorphism showed a significant association with the development of UUI among women in Lithuanian population. Women with the CC genotype of the HTR2A gene are more prone to UUI, so we believe that in order to minimize the onset of this disease in life, these women should avoid and reduce other risk factors for this disease.

Acknowledgments

Lithuanian Society of Urology, Lithuanian Society of Urogynecology, Institute of Biology Systems and Genetic Research of LUHS for advices and benevolence to implement it.

  1. Funding information: The study was supported by LUHS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  2. Author contributions: P.A. – study design, collection of data, manuscript preparation; A.P. performed statistical analysis; A.S. – genetic studies and revision of the manuscript; R.A. – collection of data and revision of the manuscript; M.J. – study design and manuscript preparation.

  3. Conflict of interest: The authors declare that there are no conflicts of interest in this work.

  4. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Received: 2020-12-15
Revised: 2021-06-04
Accepted: 2021-06-25
Published Online: 2021-08-25

© 2021 Povilas Aniulis et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/med-2021-0332
Keywords for this article
ADRB3; HTR2A; serotonin receptor 2A; gene polymorphism; UI
Creative Commons
BY 4.0

Articles in the same Issue

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  73. miR-377 inhibition enhances the survival of trophoblast cells via upregulation of FNDC5 in gestational diabetes mellitus
  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
  77. A four-lncRNA signature for predicting prognosis of recurrence patients with gastric cancer
  78. Knockdown of circ_0003204 alleviates oxidative low-density lipoprotein-induced human umbilical vein endothelial cells injury: Circulating RNAs could explain atherosclerosis disease progression
  79. Propofol postpones colorectal cancer development through circ_0026344/miR-645/Akt/mTOR signal pathway
  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
  81. COVID-19 severity in relation to sociodemographics and vitamin D use
  82. Clinical analysis of 11 cases of nocardiosis
  83. Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
  84. Four long noncoding RNAs act as biomarkers in lung adenocarcinoma
  85. Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens
  86. Relation between IL-8 level and obstructive sleep apnea syndrome
  87. circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level
  88. Nomogram prediction model for renal anaemia in IgA nephropathy patients
  89. Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis
  90. NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma
  91. A nomogram for predicting metabolic steatohepatitis: The combination of NAMPT, RALGDS, GADD45B, FOSL2, RTP3, and RASD1
  92. Clinical and prognostic features of MMP-2 and VEGF in AEG patients
  93. The value of miR-510 in the prognosis and development of colon cancer
  94. Functional implications of PABPC1 in the development of ovarian cancer
  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
  97. Prediction of improvement after anterior cruciate ligament reconstruction
  98. Effluent Osteopontin levels reflect the peritoneal solute transport rate
  99. circ_0038467 promotes PM2.5-induced bronchial epithelial cell dysfunction
  100. Significance of miR-141 and miR-340 in cervical squamous cell carcinoma
  101. Association between hair cortisol concentration and metabolic syndrome
  102. Microvessel density as a prognostic indicator of prostate cancer: A systematic review and meta-analysis
  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
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