Effect of VNTR Polymorphism of the AS3MT Gene and Obstetrical Complications on the Severity of Schizophrenia

Korovaitseva, G. I.; Gabaeva, M. V.; Yunilainen, O. A.; Голимбет, В. Е.

doi:10.1007/s10517-019-04653-3

Cited by 6 publications

(7 citation statements)

References 6 publications

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“…Data on environmental risk factors, depression, and SIB were obtained only for patients. The extended sample overlapped with the sample from our previous study of the VNTR [ 25 ]. Demographic and clinical characteristics of participants are presented in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA from peripheral blood leukocytes was extracted by the standard phenol-chloroform method. Genotyping was performed using real-time PCR by C1000 Touch system (Bio-Rad, Hercules, CA, USA), with primers and reaction conditions described earlier [ 25 ]. The PCR fragments with two (419 bp, allele V2) and three (455 bp, allele V3) repeats were separated in an 8% PAAG.…”

Section: Methodsmentioning

confidence: 99%

“…Prior research [ 22 , 23 ] has shown that the VNTR regulates the alternative splicing of a brain-unique isoform AS3MT d2d3 lacking arsenite methyltransferase activity; this isoform has higher levels in individuals with schizophrenia compared to controls; it is upregulated during human stem cell differentiation toward neuronal fates; and it reduces densities of mushroom dendritic spines in cultured primary hippocampal neurons. In addition, the VNTR predicts DNAm within the AS3MT gene [ 22 ], influences brain activation of the prefrontal and cingulate cortex during a working memory task [ 24 ], and has shown an interaction effect with obstetric complications on negative symptoms in women with schizophrenia [ 25 ]. The similar effects of the local and VNTR genotypes on DNAm and behavior could be expected owing to the strong LD.…”

Section: Introductionmentioning

confidence: 99%

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A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia

Алфимова

Kondratyev

Korovaitseva

et al. 2022

IJMS

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As genetic and environmental influences on schizophrenia might converge on DNA methylation (DNAm) within loci which are both associated with the disease and implicated in response to environmental stress, we examined whether DNAm within CYP17A1, a hypothalamus–pituitary–adrenal axis gene which is situated within the schizophrenia risk locus 10q24.32, would mediate genetic and environmental effects on stress-related schizophrenia symptoms. DNAm within an exonic–intronic fragment of CYP17A1 was assessed in the blood of 66 schizophrenia patients and 63 controls using single-molecule real-time bisulfite sequencing. Additionally, the VNTR polymorphism of the AS3MT gene, a plausible causal variant within the 10q24.32 locus, was genotyped in extended patient and control samples (n = 700). The effects of local haplotype, VNTR and a polyenviromic risk score (PERS) on DNAm, episodic verbal memory, executive functions, depression, and suicidality of patients were assessed. Haplotype and PERS differentially influenced DNAm at four variably methylated sites identified within the fragment, with stochastic, additive, and allele-specific effects being found. An allele-specific DNAm at CpG-SNP rs3781286 mediated the relationship between the local haplotype and verbal fluency. Our findings do not confirm that the interrogated DNA fragment is a place where genetic and environmental risk factors converge to influence schizophrenia symptoms through DNAm.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia

Алфимова

Kondratyev

Korovaitseva

et al. 2022

IJMS

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“…Furthermore, AS3MT has been found to be upregulated and negatively correlated with antioncogene mir‐548c‐3p in arsenic‐exposed population 15,16 . Subsequent study found that AS3MT, previously CYT19, was located in the chromosome 10q24.32 as a potential risk factor for the progression schizophrenia 17 . However, Locus 10q24.32 contained typical tumor‐related genes, including FGF8 and NPM3 18 .…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Subsequent study found that AS3MT, previously CYT19, was located in the chromosome 10q24.32 as a potential risk factor for the progression schizophrenia. 17 However, Locus 10q24.32 contained typical tumor-related genes, including FGF8 and NPM3. 18 These results indicated that AS3MT is not only involved in arsenic metabolism, but also could be involved in the progression of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Inorganic arsenic‐mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes

Sun

Tan

Wang

et al. 2020

Environmental Toxicology

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Long‐term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non‐small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO2) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA‐mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes.

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Involvement of a AS3MT/c‐Fos/p53 signaling axis in arsenic‐induced tumor in human lung cells

Sun

Cheng

Tang

et al. 2022

Environmental Toxicology

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Arsenite methyltransferase (AS3MT) is an enzyme that catalyzes the dimethylation of arsenite (+3 oxidation state). At present, the studies on arsenic carcinogenicity mainly focus on studying the polymorphisms of AS3MT and measuring their catalytic activities.We recently showed that AS3MT was overexpressed in lung cancer patients who had not been exposed to arsenic. However, little is known about the molecular mechanisms of AS3MT in arsenite-induced tumorigenesis. In this study, we showed that AS3MT protein expression was higher in the arsenic-exposed population compared to the unexposed population. AS3MT was also overexpressed in human lung adenocarcinoma (A549) and human bronchial epithelial (16HBE) cells exposed to arsenic (A549: 20-60 μmol/L; 16HBE: 2-6 μmol/L) for 48 h. Furthermore, we investigated the effects of AS3MT on cell proliferation and apoptosis using siRNA. The downregulation of AS3MT inhibited the proliferation and promoted the apoptosis of cells. Mechanistically, AS3MT was found to specifically bind to c-Fos, thereby inhibiting the binding of c-Fos to c-Jun.Additionally, the siRNA-mediated knockdown of AS3MT enhanced the phosphorylation of Ser392 in p53 by upregulating p38 MAPK expression. This led to the activation of p53 signaling and the upregulated expression of downstream targets, such as p21, Fas, PUMA, and Bax. Together, these studies revealed that the inorganic arsenic-mediated upregulation of AS3MT expression directly affected the proliferation and apoptosis of cells, leading to arsenic-induced toxicity or carcinogenicity.

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Effect of VNTR Polymorphism of the AS3MT Gene and Obstetrical Complications on the Severity of Schizophrenia

Cited by 6 publications

References 6 publications

A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia

A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia

Inorganic arsenic‐mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes

Involvement of a AS3MT/c‐Fos/p53 signaling axis in arsenic‐induced tumor in human lung cells

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