Sex-dependent effect on the association of COMT Val158Met polymorphism with schizophrenia clinical symptoms and cognitive impairment

doi:10.21203/rs.3.rs-817886/v1

Catechol-O-methyltransferase (COMT) Val¹⁵⁸Met (rs4680) polymorphism is thought to be involved in the pathogenesis of schizophrenia, which is related to the regulation of dopamine transmission in the prefrontal cortex. Recent studies have shown that the influence of COMT Val¹⁵⁸Met variation is sexually dimorphic. This study aims to explore the possible effect of the interaction between COMT Val¹⁵⁸Met polymorphism and sex on patients’ clinical characteristics and cognitive function. 367 inpatients with chronic schizophrenia (246 males and 121 females) and 419 healthy controls (172 males and 247 females) are recruited. The cognitive performances are assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the COMT Val¹⁵⁸Met polymorphism is genotyped. The psychopathological symptoms of the patients are assessed by the Positive and Negative Syndrome Scale (PANSS). We find that: 1) sex difference in the allele frequency and genotype distribution of COMT Val¹⁵⁸Met are found only in schizophrenia patients; 2) there is sex × COMT genotype interaction in positive symptoms, immediate memory, attention, and RBANS total score indexes in patients with schizophrenia; 3) mainly in the male patients’ sample, Val/Val carriers exhibit more positive symptoms and more severe cognitive impairment than Met carriers. These findings suggest that COMT Val¹⁵⁸Met polymorphism is associated with the risk and severity of schizophrenia in a sexually dimorphic way, which is helpful to understand the factors that may lead to different manifestations of male and female patients with schizophrenia.

Molecular Biology

Schizophrenia

Catechol-O-methyl transferase (COMT)

Val158Met (rs4680)

Sex difference

Cognitive function

Schizophrenia is a devastating mental disorder, with a lifetime prevalence rate of approximately 0.4% worldwide [1]. The burden of disease is high, however, the biological background of the pathophysiology of schizophrenia has not been fully understood [1, 2]. The core features of schizophrenia are characterized by three domains, including heterogeneous positive and negative symptoms (such as hallucinations, delusions, and reduced expression of emotions or motivation), and cognitive dysfunction (such as difficulties with concentration, working memory, and decision making) [3].

Furthermore, sex differences in schizophrenia have also received attention in terms of age of onset, course of the disease, symptomatology, treatment outcome, and neurological abnormalities [4–6]. There is evidence that the risk ratio of men suffering from schizophrenia is about 1.4 times higher than that of women [2, 7]. In terms of clinical symptoms, male patients exhibit more negative symptoms, while female patients display more affective, paranoid, and periodic psychiatric symptoms [4]. The underlying molecular mechanism of sex differences for the features of schizophrenia remains unclear.

Several candidate genes are associated with sexual dimorphism in schizophrenia, including the catechol-O-methyl transferase (COMT) Val¹⁵⁸Met gene (Bollettini et al. 2018). A large amount of evidence indicates that COMT encodes a major catabolic enzyme involved in DA metabolism and has been widely studied in patients with schizophrenia. The human COMT gene is located at position 11.21 on chromosome 22, which is a region closely related to mental illness. Single nucleotide polymorphism (SNP) rs4680 (Val¹⁵⁸Met) is one of the widely studied polymorphisms of the COMT gene, which transforms from valine (or allele G) to methionine (or allele A) (Val¹⁵⁸Met). COMT Val¹⁵⁸Met regulates the dopaminergic transmission in the prefrontal cortex (PFC), where it accounts for more than 60% of the metabolic degradation of dopamine [8]. At normal body temperature, the COMT activity of Val allele carriers is three times higher than that of Met allele carriers. Higher COMT activity leads to lower DA signal, so the Val allele may cause physiological impairment of the prefrontal lobe [9]. Given the importance of COMT in regulating dopamine, the COMT Val¹⁵⁸Met gene polymorphism has been associated with dopamine-related disorder (such as schizophrenia) and cognitive dysfunction, and the response to treatment [10, 11]. For example, Val/Val patients with schizophrenia show more severe psychiatric symptoms [12],more positive/negative symptoms [13–15], and worse performance in working memory tasks [16]. Met allele load can predict improvement in cognitive performance and positive/negative symptoms after antipsychotic treatment [12, 17, 18]. COMT is considered to have sex-specific effects on various transcriptional regulation of estrogens and other mechanisms [19]. Recent studies have reported the sexually dimorphic effect of Val¹⁵⁸Met polymorphism on brain morphology. The decrease in COMT enzyme activity increases the thickness of PFC in male, but not female mice and humans [20, 21]. Consistent with neuroanatomical changes, COMT Val¹⁵⁸Met polymorphism is associated with sex differences in PFC-dependent working memory in patients, which means that men with Met allele show better working memory [21]. It has also been reported that there is an effect of high-activity allele loading on negative symptoms, disorganization, and cognition (such as executive function and verbal IQ) in males [22, 23], while the Met allele is associated with lower stress effects in females [24].

In addition to the sex factor, ethnicity seems like also an influencing factor considering the relationship between COMT Val¹⁵⁸Met polymorphism and schizophrenia. A recent meta-analysis of 32816 subjects indicates an association between COMT Val¹⁵⁸Met polymorphism and schizophrenia in the general population. The risk is higher in Caucasians than in Asians [25]. However, studies in the Chinese Han population have found inconsistent results between Val¹⁵⁸Met polymorphism and schizophrenia. For example. Sun et al. found no significant genotypic association between Val¹⁵⁸Met polymorphism and clinical symptoms or cognitive function [26], while Li et al. found that Val¹⁵⁸Met polymorphism may be associated with negative symptoms of schizophrenia in Han Chinese. [13, 27]. One possible reason for this inconsistency is that many of these studies do not consider the sex-gene interaction [26, 28]. Therefore, at present, there is no study from China to investigate the effect of sex × COMT genotype interaction on symptoms and cognitive function in patients with schizophrenia.

Based on the above background, this study aims to explore the effect of sex × COMT genotype interaction on the characteristics and cognitive function of Chinese Han patients with schizophrenia.

Subjects

We recruited 367 inpatients (246 males and 121 females）from the Beijing Huilongguan Hospital, a Beijing city-owned psychiatric hospital. These patients were all Han Chinese and met the criteria for schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). The diagnosis was independently confirmed by two experienced psychiatrists. The patients met the following criteria: a) aged between 20 to 75 years old, with more than five years of education; b) had a course of disease for at least 5 years; c) received a stable dose of oral antipsychotic drugs for more than one year. Antipsychotic treatment was monotherapy, including clozapine (47.5%), risperidone (25.0%), chlorpromazine (4.9%), sulpiride (8.2%), perphenazine (6.6%), haloperidol (4.5%), nimesulide (2.9%), and quetiapine (0.4%). We excluded patients with major physical diseases or any acute or chronic diseases affecting the immune, endocrine, metabolic or nervous systems (such as cerebrovascular disease, cancer, lung disease, or diabetes), as well as pregnant or breast-feeding women. Their average age was 50.16 ± 9.80 years (ranging from 19 to 73 years), and their average course of the disease was 27.66 ± 7.79 years (ranging from 14 to 55 years). The average education level was 9.71 ± 2.52 years. 181 males and 63 females of those patients completed the cognition assessment. In the same period, a total of 419 healthy Han Chinese was recruited from the local area in Beijing, including 172 males and 247 females. Any healthy subjects with a history of medical abnormalities or common mood disorders or substance abuse/dependence were excluded. The age, education level, marriage of patients and healthy subjects matched. Their average age was 46.21 ± 13.18 years (ranging from 16 to 70 years). The average education level was 9.2 ± 3.32 years. None of them suffered from substance/alcohol dependence/abuse except for smoking. 168 males and 229 females completed the cognitive assessment. The informed consent form was obtained from all participants. The study protocol was approved by the Institutional Review Board, Beijing Hui-Long-Guan Hospital.

Clinical assessment

Four psychiatrists simultaneously participated in a training course to evaluate the Positive and Negative Syndrome Scale (PANSS). After training, the inter-observer correlation coefficient of the PANSS total score was maintained above 0.8 to ensure the reliability and consistency of the evaluation.

The cognitive function of all subjects was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A) [29]. The clinical validity and test-retest reliability were confirmed in the Chinese general population and patients with schizophrenia [30]. It provides a total score and five subscores of cognitive function, including immediate memory, visuospatial/constructional, language, attention, and delayed memory. The Chinese version of RBANS showed good validity (Cronbach's α coefficient of the total scale, immediate memory, visuospatial, language, attention, and delayed memory were 0.9, 0.86, 0.68, 0.67, 0.85, and 0.80, respectively) and good test-retest reliability in China [30].

Blood sampling and Genotyping

After an overnight fast, venous blood was collected from the forearm vein of the subjects using the anticoagulant ethylene diamine tetraacetic acid (EDTA) tubes between 7:00 and 9:00 am. Genomic DNA was extracted from whole blood samples. Following the standard protocol, the COMT Val¹⁵⁸Met polymorphism was identified by using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) (Sequenom Inc., San Diego, CA, USA). The amplification primers were: sense: 5′-TCACCATCGAGATCAACCCC-3′, antisense: 5′-GAACGTGGTTGTAACACCTG-3′. In addition, 5% of the samples were genotyped for error checking, with a reproducibility of ＞0.99. COMT Val¹⁵⁸Met polymorphism genotyping was carried out by a technician who was blind to the clinical status of the subjects [31].

Statistical analysis

Statistical analyses were carried out using the Statistical Package of Social Sciences version 24 (SPSS, Inc., USA) for Windows. Differences between groups were compared using ANOVA/MANCOVA for continuous variables and chi-square test for categorical variables. Hardy–Weinberg equilibrium was performed to examine genotype deviation. The interaction analysis of diagnosis, sex, and COMT Val¹⁵⁸Met polymorphism on cognitive functions adopted the three-way MANCOVA, with age and education as covariates. The interaction effects of sex and genotype on cognitive functions in healthy control and patients were analyzed by two-way MANCOVA. The one-way MANCOVA was adopted to analyze the differences between genotypes of the same gender. The age, age of onset, and education were defined as covariates in the patients. Age and education were defined as covariates in healthy control. The FDR correction was performed for multiple tests and post hoc analysis. The Cohen's d method was used to calculate the standardized effect size. Descriptive summary statistics were expressed as mean ± standard deviation (SD), and differences with p＜0.05 were considered to be significant.

Demographic characteristics and genotypic data

The demographic characteristics of the subjects are shown in Table 1. One-way ANOVA indicated that there was a significant age difference (F_(1,781) =32.83, p<0.01), but not in education between patients and healthy controls. In addition, there was a significant sex difference in age in the healthy control group (F_(1,417) =6.59, p<0.05), and significant sex difference in educations in both healthy control and patients (F_(1,413) =4.17, p<0.05; F_(1,365) =5.35, p<0.05). There was no significant difference in the age of onset between male patients and female patients.

The COMT Val¹⁵⁸Met genotype distribution was consistent with Hardy–Weinberg equilibrium in healthy controls (c²=2.83, df=1, p=0.24) and patients (c²=0.03, df=1, p=0.98). The distribution of COMT Val¹⁵⁸Met genotype and allele were summarized in Table 1.There was no significant difference in COMT Val¹⁵⁸Met genotype (c²=2.27, df=2, p＞0.05) and allele distribution (c²=0.52, df=1, p＞0.05) between the healthy controls and patients. However, there were significant sex differences in the COMT Val¹⁵⁸Met genotype (c²=10.3, df=2, p<0.01) and allele frequency in patients (c²=4.16, df=1, p<0.05), showing that male patients had a higher proportion of Met alleles. However, there was no such a sex difference in healthy controls (c²=0.82, df=2, p＞0.05; c²=0.03, df=1, p＞0.05, respectively).

Interaction of diagnosis, sex and COMT Val¹⁵⁸Met genotype on the cognitive function

As shown in Table 2, three-way MANCOVA indicated the interaction analysis results of the diagnosis, sex, and genotype. The main effects of diagnosis were significant in all cognitive indexes (all p or FDR corrected p<0.05; Cohen’s f=0.54, 0.23, 0.49, 0.30, 0.70,0.47 respectively in immediate memory, visuospatial/constructional, language, attention, delayed memory, and total score). There was significant sex effect in delayed memory (F_(1,631)=5.18, p<0.05, FDR corrected p=0.02, Cohen’s f=0.18). There was significant COMT genotype effect on language (F_(1,631)=4.92, p<0.05, FDR corrected p=0.03, Cohen’s f=0.18). There was significant diagnosis×sex interaction in delayed memory (F_(1,631)=5.58, p<0.05, FDR corrected p=0.09, Cohen’s f=0.19), and diagnosis×COMT interaction in language (F_(1,631)=4.77, p<0.05, FDR corrected p=0.10, Cohen’s f=0.17), and sex×COMT interaction (F_(1,631)=4.54, p<0.05, FDR corrected p=0.09, Cohen’s f=0.19) in immediate memory (F_(1,631)=4.54, p<0.05, FDR corrected p=0.11, Cohen’s f=0.17), but those differences did not pass the correction.

Interaction of sex and COMT Val¹⁵⁸Met genotype on the clinical characteristics of schizophrenia patients

The interaction of sex and COMT Val¹⁵⁸Met polymorphism on the clinical characteristics of patients with schizophrenia were summarized in Table 3. After adjusting for age and education, two-way MANCOVA showed that there was a significant sex × genotype interaction effect on the positive subscale score (F_(1,238)=7.29, p<0.05, FDR corrected p=0.04, Cohen’s f=0.35), but not on the negative subscale, general psychopathology subscale or PANSS total scores (all p>0.05). In addition, there were no main effects of sex or genotype on the PANSS subscales and total scores (all p>0.05). One-way MANCOVA showed that in male patients, there was a significant genotype effect on the positive subscale (F_(1,173)=5.42, p<0.05, FDR corrected p=0.03, Cohen’s f=0.50). However, there was no genotype effect in female patients (p>0.05). Further post hoc analysis (Fig 1A) indicated that male patients with Met homozygote and heterozygote had a significantly lower score than female patients with Met homozygote and heterozygote genotypes (p<0.01 ). Male patients with Val/Val genotype had more positive symptoms than Met carriers (Val/Met vs. Met carrier: 13.3±4.8 vs. 11.6±4.6, p<0.05), while in female patients, Met carriers exhibited more positive symptoms slightly (12.3±5.4 vs. 14.7±7.3, p=0.07).

Interaction of sex and COMT Val¹⁵⁸Met genotype on cognitive performance in healthy control and schizophrenia patients

In patients, two-way MANCOVA with age, age of onset, and education as covariates indicated that there were significant sex effect on immediate memory (F_(1,235)=3.98, p<0.05, FDR corrected p=0.06, Cohen’s f=0.26), delayed memory (F_(1,235)=6.91, p<0.01, FDR corrected p=0.02, Cohen’s f=0.34), and total score (F_(1,235)=4.33, p<0.05, FDR corrected p=0.06, Cohen’s f=0.27). Moreover, there was a significant genotype effect on language (F_(1,235)=6.57, p<0.05, FDR corrected p=0.01, Cohen’s f=0.33). There was a significant sex × genotype interaction on immediate memory (F_(1,235)=4.44, p<0.05, FDR corrected p=0.07, Cohen’s f=0.33), attention (F_(1,235)=4.92, p<0.05, FDR corrected p=0.05, Cohen’s f=0.29), and total score (F_(1,235)=4.21, p<0.05, FDR corrected p=0.04, Cohen’s f=0.27).

One-way MANCOVA showed that in male patients, there was significant genotype effect on all the cognitive indexes: immediate memory (F_(1,175)= 12.9, p<0.01, FDR corrected p=0.002, Cohen’s f=0.54), visuospatial/constructional (F_(1,175)= 5.9, p<0.05, FDR corrected p=0.03, Cohen’s f=0.37), language (F_(1,175)= 4.4, p<0.05, FDR corrected p=0.05, Cohen’s f=0.32), attention (F_(1,175)=4.6, p<0.01, FDR corrected p= 0.05, Cohen’s f=0.32), delayed memory (F_(1,175)=4.3, p<0.01, FDR corrected p= 0.05, Cohen’s f=0.31), and total score (F_(1,175)=9.0, p<0.01, FDR corrected p=0.01, Cohen’s f=0.45). However, in female patients, there were no significant differences between genotypes in any of the cognitive indexes. Further post hoc analysis showed that male patients with Val homozygotes had the lowest score in nearly all the cognitive indexes (Fig1 B,C,D,E,G,F).

In the healthy controls, we did not find any significant sex effects, genotype effects, or sex × genotype interactions on cognitive performance (all p>0.05). Further post hoc analysis showed that in either male or female healthy controls, there was no significant genotype effect on any cognitive indexes (all p>0.05).

In this study, we investigate the interaction of COMT Val¹⁵⁸Met polymorphism and sex on clinical characteristics and cognitive performance of patients with schizophrenia and healthy controls in a Chinese population. The main findings of this study are as follows: 1) there are no significant differences in allele frequency and genotype distribution of COMT Val¹⁵⁸Met between healthy people and schizophrenia patients. At the same time, sex differences in the allele frequency and genotype distribution of COMT Val¹⁵⁸Met are found only in patients with schizophrenia. 2) in patients, there are sex × genotype interactions in terms of positive symptoms, immediate memory, attention, and RBANS total score. 3) in the patients’ sample, the male patients with Val/Val exhibit more positive symptoms and more severe cognitive dysfunction compared with male Met carriers.

Our results reveal that there are no significant differences in allele and genotype frequencies of COMT Val¹⁵⁸Met polymorphism between patients with schizophrenia and healthy control. This result is in line with many other studies conducted in East Asian populations [14, 32, 33]. However, the COMT Val¹⁵⁸Met polymorphism is found to play an important role in susceptibility to schizophrenia in Caucasian and African Americans [6, 10, 34, 35]. A meta-analysis report shows that there is no evidence of a significant association among the Asian populations, while the risk of disease in Caucasians with the Val allele is increased up to 10–23% [25]. These pieces of evidence suggest that the association between COMT Val¹⁵⁸Met polymorphism and schizophrenia may be race-specific. Furthermore, recent studies have shown that the genetic variations of COMT are associated with sex-dependent effects on enzyme activity, brain function, and pathological processes, suggesting that sex may be the key to understanding COMT-dependent effects [20]. In this study, we find that compared with healthy people, the distribution of Val¹⁵⁸Met gene polymorphism had significant sex differences in the allele and genotype frequencies of patients. Studies conducted in the Asian population have reached a generally consistent conclusion that COMT Val¹⁵⁸Met polymorphisms may not contribute to susceptibility to schizophrenia [26, 33]. However, previous studies may have ignored the impact of sex differences.

Previous studies have reported the potential association between COMT and negative symptoms in the Asian populations [27, 28], but some studies have not [26]. The current study does not find an association between negative symptoms and COMT in our patient samples, but COMT Val¹⁵⁸Met polymorphism has a sexually dimorphic effect on positive symptoms. Consistent with our study, Goghari et al reported that male patients with Val homozygotes demonstrated greater positive symptoms than those male patients with Met carriers [15]. The dopamine hypothesis of schizophrenia assumes that positive symptoms can be attributed to the hyperactivity of dopamine D2 receptors in the subcortical and limbic brain regions, while negative symptoms can be attributed to the hypo functionality of dopamine D1 receptors neurotransmission in PFC [36]. However, little is known about the relationship between the COMT Val¹⁵⁸Met polymorphism and dopamine receptors.

The relationship between cortical dopamine and PFC-dependent functions is inverted-U-shaped [37, 38], and too high or too low dopamine is associated with impaired function. The Val/Val genotype may be associated with a low D1/high D2 status [37]. Dopamine has been shown to play an important role in the PFC-mediated cognition [39]. Evidence from COMT knockout mice and pharmacological investigations have confirmed the importance of COMT for dopaminergic clearance in PFC [9, 20, 21]. Since the COMT efficacy of the Val alleles is three to four times higher than that of Met alleles, this difference may shape cognitive performance. In our study, male patients with homozygous Val alleles show worse cognitive performance in immediate and delayed memory, which is consistent with some previous studies. For example, Bilder et al. reported that the COMT Met allele was associated with better performance in processing speed and attention ability in patients with chronic schizophrenia [40]. Matsuzaka et al. found that Val/Val carriers scored the lowest in working memory tasks [16]. Shukla et al. found that Val homozygotes were related to poor performance on the dorsolateral-prefrontal-cortex-dependent task [41]. This sex-COMT interaction on cognitive function has also been verified in transgenic mice [42]. The activity levels of the COMT enzyme are also influenced by sex, showing that male subjects and Val alleles are associated with higher enzyme activity and possibly lower PFC dopamine levels [43]. Therefore, one possible explanation is that the co-regulation of COMT by sex and Val¹⁵⁸Met variants may lead to sex differences in schizophrenia. Although relatively little is known about how the genetic variation of Val¹⁵⁸Met affects brain structure and function, a recent study has found that male subjects with Met/Met have higher subcortical volumes [20]. Male and female patients have different association patterns between the COMT gene and disease phenotype. The COMT effect is relatively weak among women [44]. Notably, the sex-dependent effects on cognition were not observed in normal healthy people.

In summary, our results suggest that the Val allele of COMT Val¹⁵⁸Met genotype is closely associated with the positive symptoms and cognitive dysfunction of Chinese male patients with schizophrenia. There are several limitations in the current study. 1) The influence of drugs cannot be ruled out. 2) This study only examined one candidate gene, while other potential polymorphisms may be involved in the psychopathological symptoms of schizophrenia. 3) Due to the limited sample size, we cannot separate the homozygous Met/Met group and the heterozygous Val/Met group from the ‘Met allele carriers’. Therefore, larger sample size is needed to confirm our findings, and more studies are necessary to elucidate the mechanism in depth. In conclusion, this study reveals that COMT Val¹⁵⁸Met polymorphism has a sexually dimorphic effect on the severity of schizophrenia and helps to understand the factors that may lead to different manifestations between male and female patients with schizophrenia.

Contributors

Xiangyang Zhang designed the study, managed study supervision. Meihong Xiu, Dachun Chen and Yongjie Zhou interviewed the participants and conducted the clinical assessment. Hang Xu analyzed the data and drafted the manuscript. Hang Xu, Xiangyang Zhang, Weiwen Wang, Li Wang, and Jiesi Wang revised and completed the paper.

Conflict of interest

The authors declare they have no competing interests in this research.

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (81371477), China Postdoctoral Science Foundation (E0BH0110), the Special Research Assistant Program of CAS (E0ZZ0210), and the Chinese Academy of Sciences and the Key Laboratory of Mental Health, Institute of Psychology.

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Table2: Interaction of diagnosis, sex, and COMT Val¹⁵⁸Met genotype on the cognitive function

Variables	Immediate memory		Visuospatial/constructional		Language		Attention		Delayed memory		RBANS total score
	F	p	F	p	F	p	F	p	F	p	F	p
Diagnosis(D)	46.66	0.00**	7.99	0.00**	38.18	0.00**	14.61	0.00**	76.70	0.00**	34.52	0.00**
SEX	3.37	0.07	1.33	0.25	0.03	0.85	0.01	0.94	5.18	0.02*	2.54	0.11
COMT	1.15	0.28	0.02	0.90	4.92	0.03*	0.44	0.51	0.17	0.68	0.21	0.65
D×SEX	0.34	0.56	0.31	0.58	0.18	0.67	0.00	1.00	5.58	0.02*	1.44	0.23
D×COMT	1.85	0.17	0.56	0.45	4.77	0.03*	0.11	0.74	1.05	0.31	1.43	0.23
SEX×COMT	4.54	0.03*	2.97	0.09	0.53	0.46	2.68	0.10	2.62	0.11	2.40	0.12
D×SEX×BDNF	1.28	0.26	1.36	0.24	0.26	0.61	1.15	0.28	1.81	0.18	1.02	0.31

Three-way MANCOVA with age and education as the covariates; p: *<0.05，** <0.01.

Due to technical limitations, Table 1 and 3 are only available as a download in the Supplemental Files section.

Table1and3.docx

Sex-dependent effect on the association of COMT Val¹⁵⁸Met polymorphism with schizophrenia clinical symptoms and cognitive impairment

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Declarations

References

Tables

Supplementary Files

Status:

Version 1