The association between serine hydroxymethyl transferase 1 gene hypermethylation and ischemic stroke

This study aimed to determine the correlation between serine hydroxymethyl transferase 1 (SHMT1) gene methylation and ischemic stroke. A total of 202 age- and sex-matched individuals were included. Quantitative methylation-specific polymerase chain reaction (qMSP-PCR) was used to analyze the DNA methylation level. The plasma homocysteine (Hcy) concentration was much higher in ischemic cases than in controls (p = 0.009), while the HDL levels in stroke cases were considerably lower than in controls (p = 0.005). A significantly higher level of SHMT1 methylation was observed in the ischemic strokes (58.82 ± 17.83 %) compared to that in the controls (42.59 ± 20.76 %, p < 0.001). The SHMT1 methylation level was strongly correlated with HDL concentration in the healthy controls (r = 0.517, p < 0.001), while the high plasma level of Hcy showed strong association with SHMT1 methylation in ischemic strokes (r = 0.346, p < 0.001). Receiver operating characteristic (ROC) analysis of curve indicated that SHMT1 methylation have been an acceptable indicator for ischemic stroke in female patients [all sexes, area under the curve (AUC) = 0.71, p < 0.001; male patients AUC = 0.62, p = 0.032; and female patients AUC = 0.79, p < 0.001] and in all ages (AUC = 0.71, p < 0.001). In our samples, DNA methylation levels of the STHMI gene were significantly correlated with ischemic stroke in Han Chinese. STHMI hypermethylation was significantly associated with the high Hcy concentration in ischemic stroke and had value as a potential indicator for female ischemic stroke.

Download Full-text

DNA methylation of AHCY may increase the risk of ischemic stroke

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2020.4535 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lei Zhao ◽

Xiaosheng Chen ◽

Shengjun Zhou ◽

Zhiqing Lin ◽

Xi Yu ◽

...

Keyword(s):

Dna Methylation ◽

Ischemic Stroke ◽

Methylation Level ◽

Age Groups ◽

Area Under The Curve ◽

Methylation Pattern ◽

Control Group ◽

Case Group ◽

Roc Curve Analysis ◽

Gene Encoding

Genetic factors play an important role in the pathogenesis of ischemic stroke. Of these, epigenetic modifications provide a new direction for the study of ischemic stroke pathogenesis. This study aimed to determine the correlation between DNA methylation of the gene encoding S-adenosylhomocysteine hydrolase (AHCY) and the risk of ischemic stroke in 64 ischemic stroke patients and 138 patients with traumatic brain injury (control group). The methylation level of AHCY was analyzed using quantitative methylation-specific polymerase chain reaction. Statistically significant differences in AHCY methylation levels were observed between the case group [medians (interquartile range): 0.13% (0.09%, 0.27%)] and the control group [0.06% (0.00%, 0.17%), p < 0.0001], and these associations remained significant in both male (p = 0.003) and female (p = 0.0005) subjects. A subgroup analysis by age revealed a considerably higher percentage of methylated AHCY in the case group than the control group in all age groups (age < 60 years, p = 0.007; age ≥ 60 years, p < 0.0001). A receiver operating characteristic (ROC) curve analysis revealed a trend toward a role for AHCY methylation as an indicator of risk in all ischemic patients [area under the curve (AUC) = 0.70, p = 0.0001], male patients (AUC = 0.67, p = 0.004), and female patients (AUC = 0.75, p = 0.0002). Our study confirmed a significant association between the AHCY DNA methylation level and the risk of ischemic stroke, suggesting that this gene methylation pattern may be a potential diagnostic marker of ischemic stroke.

Download Full-text

GPX3 methylation is associated with hematologic improvement in low-risk myelodysplastic syndrome patients treated with Pai-Neng-Da

Journal of International Medical Research ◽

10.1177/0300060520956894 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052095689

Author(s):

Shujun Yang ◽

Tong Gao ◽

Zhonghua Zheng ◽

Binbin Lai ◽

Lixia Sheng ◽

...

Keyword(s):

Clinical Trial ◽

Myelodysplastic Syndrome ◽

Methylation Level ◽

Hematological Parameters ◽

Low Risk ◽

Controlled Clinical Trial ◽

Platelet Response ◽

Female Patients ◽

Platelet Counts ◽

Male Patients

Objective The aim of this prospective randomized controlled clinical trial was to explore the relationship between GPX3 methylation and Pai-Neng-Da (PND) in the treatment of patients with low-risk myelodysplastic syndrome (MDS). Methods There were 82 low-risk MDS patients who were randomly divided into the following two groups: androl, thalidomide, and PND capsule (ATP group, n = 41); or androl and thalidomide (AT group, n = 41). Hemoglobin and neutrophil and platelet counts and changes in GPX3 methylation level were assessed. Results The plasma hemoglobin level increased in both groups after treatment. However, the platelet count increased only in the ATP group. Patients in the ATP group had a better platelet response than the AT group, and GPX3 methylation markedly decreased after treatment with ATP but not after treatment with AT. Moreover, male patients had a significantly lower GPX3 methylation level than female patients, while platelet counts from male patients increased dramatically after the ATP regimens compared with female patients. GPX3 methylation changes were negatively correlated with platelet changes in ATP group. Conclusion PND can improve hematological parameters and decrease the GPX3 methylation level. Decreasing GPX3 methylation is associated with the hematologic response that includes platelet in GPX3 methylation. China Clinical Trial Bureau (ChiCTR; http://www.chictr.org.cn/ ) registration number: ChiCTR-IOR-15006635.

Download Full-text

The Competition between DNA Methylation and Demethylation is Associated with Transcription Regulation and Tumorigenesis

10.21203/rs.3.rs-123209/v1 ◽

2021 ◽

Author(s):

Wei Li ◽

Jiejun Shi ◽

Jianfeng Xu ◽

Yiling Chen ◽

Jingyi Jessica Li ◽

...

Keyword(s):

Dna Methylation ◽

Transcription Regulation ◽

Tumor Suppressor Genes ◽

Strong Association ◽

Promoter Hypermethylation ◽

Dna Methyltransferases ◽

Chromatin Accessibility ◽

Strongly Correlated ◽

Average Methylation ◽

Tet Enzymes

Abstract The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, their competition effect remains elusive. Here, we quantify the competition between DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying methylation competition by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation competition is strongly correlated with gene expression. In particular, during tumorigenesis, the elevation of methylation competition is associated with the repression of 40 ~ 60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation competition can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation competition represents a novel methylation metric important for transcription regulation and tumorigenesis and is largely distinct from conventional metrics, such as average methylation and methylation variation.

Download Full-text

Pan-Cancer Analysis of FURIN as a Potential Prognostic and Immunological Biomarker

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.648402 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bolun Zhou ◽

Shugeng Gao

Keyword(s):

Dna Methylation ◽

Immune Checkpoint ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Strong Association ◽

Strongly Correlated ◽

Calcium Dependent ◽

Free Interval ◽

Tumor Mutational Burden ◽

Pan Cancer

BackgroundFurin is a calcium-dependent protease that processes various precursor proteins through diverse secretory pathways. The deregulation of FURIN correlated with the prognosis of patients in numerous diseases. However, the role of FURIN in human pan-cancer is still largely unknown.MethodsMultiple bioinformatic methods were employed to comprehensively analyze the correlation of FURIN expression with prognosis, mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, tumor immune infiltration, and common immune checkpoint inhibitors (ICIs) from the public database, and aim to evaluate the potential prognostic value of FURIN across cancers.ResultsFURIN was aberrantly expressed and was strongly correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Moreover, survival analysis across cancers revealed that FURIN expression was correlated with overall survival (OS) in four cancers, disease-specific survival (DSS) in five cancers, progression-free interval (PFI) in seven cancers, and disease-free interval (DFI) in two cancers. Also, FURIN expression was related to immune cell infiltration in 6 cancers and ImmuneScore/StromalScore in 10 cancers, respectively. In addition, FURIN expression also showed strong association between expression levels and immune checkpoint markers in three cancers.ConclusionFURIN can serve as a significant prognostic biomarker and correlate with tumor immunity in human pan-cancer.

Download Full-text

DNA methylation array analyses to identify HYAL2 methylation in peripheral blood as a marker for the detection of early breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.26 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 26-26

Author(s):

Rongxi Yang ◽

Katrin Pfuetze ◽

Manuela Zucknick ◽

Christian Sutter ◽

Frederik Marme ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

T Cells ◽

Peripheral Blood ◽

Methylation Level ◽

Cpg Island ◽

Early Stage ◽

Strong Association ◽

Cell Type ◽

Increased Risk

26 Background: Early detection is crucial to improve the survival rate and quality of life of breast cancer (BC) patients. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. We aim to identify BC-associated DNA methylation signatures in peripheral blood. Methods: We identified a BC-associated differentially methylated locus by genome-wide investigation using Illumina 27K Methylation Assay. Two validation studies and replications in leucocytes and T cells were carried out using MassARRAY. The RNA expression levels were measured by real-time PCR. Results: The methylation level of CpG site cg27091787 in hyaluronoglucosaminidase 2 gene (HYAL2) in peripheral blood was significantly lower in BC cases than in controls (discovery round, 72 BC case and 24 controls, p = 2.61 × 10-9 adjusted for cell-type proportions; first validation round,338 BC case and 507 controls, p < 0.0001; second validation round,189 BC case and 189 controls, p < 0.0001). Compared to the highest quartile, the lowest quartile of cg27091787 methylation was associated with a more than 40-fold increased risk of BC (p < 0.0001). In addition to cg27091787, the decreased methylation of a 650 bp CpG island shore of HYAL2 was also associated with BC. Moreover, the expression and methylation of HYAL2 in leucocytes were inversely correlated (p = 0.006). To note, the BC-associated decreased HYAL2 methylation was replicated in T cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early stage BC cases from healthy controls (area under curve (AUC) = 0.88), and was also robust for the detection of BC in younger women (AUC = 0.87). Conclusions: Validating the epigenome-wide study by independent cohorts, we have revealed a strong association between decreased HYAL2 methylation in peripheral blood and BC. Our results have given an answer to the debate on the origin of BC-associated differential methylation in blood, which is not only because of the change of cell type proportions, but more importantly due to altered methylation in specific blood cell fragments, like in T cells. And thus, we provide a promising blood-based marker for the detection of early BC.

Download Full-text

The concurrence of DNA methylation and demethylation is associated with transcription regulation

Nature Communications ◽

10.1038/s41467-021-25521-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jiejun Shi ◽

Jianfeng Xu ◽

Yiling Elaine Chen ◽

Jason Sheng Li ◽

Ya Cui ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transcription Regulation ◽

Strong Association ◽

Promoter Hypermethylation ◽

Dna Methyltransferases ◽

Chromatin Accessibility ◽

Strongly Correlated ◽

Average Methylation ◽

Tet Enzymes

AbstractThe mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying ‘methylation concurrence’ by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.

Download Full-text

Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

10.1101/2021.02.02.21249720 ◽

2021 ◽

Author(s):

Hanna Nowotny ◽

Matthias K. Auer ◽

Christian Lottspeich ◽

Heinrich Schmidt ◽

Ilja Dubinski ◽

...

Keyword(s):

Diurnal Rhythm ◽

Area Under The Curve ◽

Early Morning ◽

Hydroxylase Deficiency ◽

Cross Sectional ◽

Female Patients ◽

Male Patients ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency ◽

Monitoring Treatment

AbstractContextSeveral studies have highlighted the importance of the 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as potential biomarkers for monitoring patients with 21-hydroxylase deficiency (21OHD).ObjectiveTo analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD.Design, Setting, and ParticipantsCross-sectional single center study including 34 patients with classic 21OHD (men=14; women=20) and 32 BMI- and age-matched controls (men=15; women=17).Outcome MeasuresSalivary concentrations of the following steroids were analyzed by LC-MS/MS: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11β-hydroxyandrostenedione (11OHA4) and 11-ketotestosterone (11KT).ResultsSimilar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: male patients Δmean = 79 %; male controls Δmean = 81%; female patients Δmean = 33 %; female controls Δmean = 91 %; 11KT: male patients Δmean = 64 %; male controls Δmean = 60 %; female patients Δmean = 49 %; female controls Δmean = 81 %). Significant correlations between the area under the curve (AUC) for 17OHP and 11KT (r(p)male = 0.741**; r(p)female = 0.842****), and 11OHA4 (r(p)male = 0.385n.s.; r(p)female = 0.527*) were observed in patients but not in controls.ConclusionsAdrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

Download Full-text

Variation of Autonomic Nervous System Function by Age and Gender in Thai Ischemic Stroke Patients

Brain Sciences ◽

10.3390/brainsci11030380 ◽

2021 ◽

Vol 11 (3) ◽

pp. 380

Author(s):

Warawoot Chuangchai ◽

Wiraporn Pothisiri ◽

Phumdecha Chanbenjapipu

Keyword(s):

Nervous System ◽

Ischemic Stroke ◽

Autonomic Nervous System ◽

Elderly Patients ◽

Parasympathetic Nervous System ◽

Pulse Transit Time ◽

Stroke Patients ◽

Autonomic Nervous ◽

Female Patients ◽

Male Patients

Background: Ischemic stroke is one of the major causes of disability and mortality. Its effects on the autonomic nervous system (ANS) through nonlinear heart rate variability (HRV) and pulse transit time (PTT) have not been well explored among Thai patients. Objective: This study aims to demonstrate the association between ANS and ischemic stroke through nonlinear HRV and PTT. Methods: In total, 111 patients were enrolled in the study and their short-term HRV and PTT data were collected. Results: Parasympathetic tone was higher in elderly patients (≥60 years). The elderly patients had a higher SD1 but lower SD2 and SD2/SD1 than the younger patients, and a similar pattern was found in the female patients compared to the male patients. These findings were supported by the results of the Poincaré plots. Older and female patients had circular plots and approximately round plots, respectively. Moreover, the parasympathetic nervous system (PNS) response was moderate and positively associated with SD1 (r = 0.47, p < 0.001) and PTT (r = 0.29, p = 0.002), and negatively associated with SD2 and SD2/SD1 (r = −0.47, p < 0.001), after controlling for age and sex. Conclusions: The PNS response was predominant in older and female patients whereas the sympathetic response was lower than in the younger and male patients, which reflected certain characteristics of ANS response to ischemic stroke. Moreover, nonlinear parameters of SD1, SD2, SD2/SD1, and Poincaré plots including PTT are useful and recommended in investigating ANS, particularly in PNS, among ischemic stroke patients.

Download Full-text

Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab446 ◽

2021 ◽

Author(s):

Hanna Franziska Nowotny ◽

Matthias K Auer ◽

Christian Lottspeich ◽

Heinrich Schmidt ◽

Ilja Dubinski ◽

...

Keyword(s):

Diurnal Rhythm ◽

Area Under The Curve ◽

Early Morning ◽

Adrenal Hyperplasia ◽

Treatment Control ◽

Cross Sectional ◽

Female Patients ◽

Single Center Study ◽

Male Patients ◽

Monitoring Treatment

Abstract Context Several studies have highlighted the importance of the 11oxygenated 19carbon (11oxC19) adrenalderived steroids as potential biomarkers for monitoring patients with 21hydroxylase deficiency (21OHD). Objective To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD. Design, Setting, and Participants Cross-sectional single center study including 59 patients with classic 21OHD (men=30; women=29) and 49 BMI- and agematched controls (men=19; women=30). Outcome Measures Salivary concentrations of the following steroids were analyzed by LCMS/MS: 17hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11βhydroxyandrostenedione (11OHA4) and 11ketotestosterone (11KT). Results Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: mean reduction of hormone concentrations between timepoint one and five (Δmean) in male patients = 66 %; male controls Δmean = 83 %; female patients Δmean = 47 %; female controls Δmean = 86 %; 11KT: male patients Δmean = 57 %; male controls Δmean = 63 %; female patients Δmean = 50 %; female controls Δmean = 76 %). Significant correlations between the area under the curve (AUC) for 17OHP and 11KT (r pmale = 0.773 <0.0001; r pfemale = 0.737 <0.0001), and 11OHA4 (r pmale = 0.633 0.0002; r pfemale = 0.564 0.0014) were observed in patients but not present or reduced in controls. Conclusions Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

Download Full-text

Evaluation of the clot burden score (cbs) for acute ischemic stroke (ais) in intent-to-treat patients.

Journal Of Cardiovascular, Neurovascular & Stroke ◽

10.32896/cvns.v1n1.11-15 ◽

2019 ◽

Vol 1 (1) ◽

pp. 11-15 ◽

Cited By ~ 1

Author(s):

Sarah Yaziz ◽

Ahmad Sobri Muda ◽

Wan Asyraf Wan Zaidi ◽

Nik Azuan Nik Ismail

Keyword(s):

Ischemic Stroke ◽

Clinical Outcome ◽

Acute Ischemic Stroke ◽

Predictive Value ◽

Area Under The Curve ◽

Rank Correlation ◽

Treatment Decision ◽

Roc Curves ◽

Significant Negative Correlation ◽

Clot Burden

Background : The clot burden score (CBS) is a scoring system used in acute ischemic stroke (AIS) to predict patient outcome and guide treatment decision. However, CBS is not routinely practiced in many institutions. This study aimed to investigate the feasibility of CBS as a relevant predictor of good clinical outcome in AIS cases. Methods: A retrospective data collection and review of AIS patients in a teaching hospital was done from June 2010 until June 2015. Patients were selected following the inclusion and exclusion criteria. These patients were followed up after 90 days of discharge. The Modified Rankin scale (mRS) was used to assess their outcome (functional status). Linear regression Spearman Rank correlation was performed between the CBS and mRS. The quality performance of the correlations was evaluated using Receiver operating characteristic (ROC) curves. Results: A total of 89 patients with AIS were analysed, 67.4% (n=60) male and 32.6% (n=29) female. Twenty-nine (29) patients (33.7%) had a CBS ?6, 6 patients (6.7%) had CBS <6, while 53 patients (59.6%) were deemed clot free. Ninety (90) days post insult, clinical assessment showed that 57 (67.6%) patients were functionally independent, 27 (30.3%) patients functionally dependent, and 5 (5.6%) patients were deceased. Data analysis reported a significant negative correlation (r= -0.611, p<0.001). ROC curves analysis showed an area under the curve of 0.81 at the cut-off point of 6.5. This showed that a CBS of more than 6 predicted a good mRS clinical outcome in AIS patients; with sensitivity of 98.2%, specificity of 53.1%, positive predictive value (PPV) of 76%, and negative predictive value (NPV) of 21%. Conclusion: CBS is a useful additional variable for the management of AIS cases, and should be incorporated into the routine radiological reporting for acute ischemic stroke (AIS) cases.

Download Full-text