Novel DNA methylation sites of glucose and insulin homeostasis: an integrative cross-omics analysis

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of the functional relevance of the phenomenon remains limited. Because obesity is the main risk factor for T2D and a driver of methylation from previous study, we aimed to explore the effect of DNA methylation in the early phases of T2D pathology while accounting for body mass index (BMI). We performed a blood-based epigenome-wide association study (EWAS) of fasting glucose and insulin among 4,808 non-diabetic European individuals and replicated the findings in an independent sample consisting of 11,750 non-diabetic subjects. We integrated blood-based in silico cross-omics databases comprising genomics, epigenomics and transcriptomics collected by BIOS project of the Biobanking and BioMolecular resources Research Infrastructure of the Netherlands (BBMRI-NL), the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and the tissue-specific Genotype-Tissue Expression (GTEx) project. We identified and replicated nine novel differentially methylated sites in whole blood (P-value < 1.27 × 10-7): sites in LETM1, RBM20, IRS2, MAN2A2 genes and 1q25.3 region were associated with fasting insulin; sites in FCRL6, SLAMF1, APOBEC3H genes and 15q26.1 region were associated with fasting glucose. The association between SLAMF1, APOBEC3H and 15q26.1 methylation sites and glucose emerged only when accounted for BMI. Follow-up in silico cross-omics analyses indicate that the cis-acting meQTLs near SLAMF1 and SLAMF1 expression are involved in glucose level regulation. Moreover, our data suggest that differential methylation in FCRL6 may affect glucose level and the risk of T2D by regulating FCLR6 expression in the liver. In conclusion, the present study provided nine new DNA methylation sites associated with glycemia homeostasis and also provided new insights of glycemia related loci into the genetics, epigenetics and transcriptomics pathways based on the integration of cross-omics data in silico.

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UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes

Translational Psychiatry ◽

10.1038/s41398-021-01378-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cristina Rodriguez-Fontenla ◽

Angel Carracedo

Keyword(s):

In Silico ◽

Association Studies ◽

Meta Analysis ◽

Neurodevelopmental Disorder ◽

Gastrointestinal Symptoms ◽

Tissue Expression ◽

Autism Spectrum ◽

Biological Characterization ◽

Large Size ◽

Body Tissues

AbstractAutism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.

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Effect of folate supplementation on insulin sensitivity and type 2 diabetes: a meta-analysis of randomized controlled trials

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy234 ◽

2019 ◽

Vol 109 (1) ◽

pp. 29-42 ◽

Cited By ~ 13

Author(s):

Mads Vendelbo Lind ◽

Lotte Lauritzen ◽

Mette Kristensen ◽

Alastair B Ross ◽

Jane Nygaard Eriksen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Randomized Controlled Trials ◽

Fasting Glucose ◽

Meta Analysis ◽

Controlled Trials ◽

Folate Supplementation ◽

Randomized Controlled ◽

Meta Analyses

ABSTRACT Background Various mechanisms link higher total homocysteine to higher insulin resistance (IR) and risk of type 2 diabetes (T2D). Folate supplementation is recognized as a way to lower homocysteine. However, randomized controlled trials (RCTs) show inconsistent results on IR and T2D outcomes. Objective The aim of this study was to examine the effect of folate supplementation on IR and T2D outcomes. Design We conducted a systematic literature search in PubMed, Web of Science, and EMBASE and prior systematic reviews and meta-analyses and identified 29 RCTs (22,250 participants) that assessed the effect of placebo-controlled folate supplementation alone or in combination with other B vitamins on fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), or risk of T2D. The meta-analysis was conducted using both random- and fixed-effects models to calculate weighted mean differences (WMDs) or risk ratios with 95% CIs. Subgroup analyses were conducted based on intervention type (folate alone or in combination with other B vitamins), as well as analysis based on population characteristics, duration, dose, and change in homocysteine. Results When compared with placebo, folate supplementation lowered fasting insulin (WMD: −13.47 pmol/L; 95% CI: −21.41, −5.53 pmol/L; P < 0.001) and HOMA-IR (WMD: −0.57 units; 95% CI: −0.76, −0.37 units; P < 0.0001), but no overall effects were observed for fasting glucose or HbA1c. Heterogeneity was low in all meta-analyses, and subgroup analysis showed no signs of effect modification except for change in homocysteine, with the most pronounced effects in trials with a change of >2.5 µmol/L. Changes in homocysteine after folate supplementation correlated with changes in fasting glucose (β = 0.07; 95% CI: 0.01, 0.14; P = 0.025) and HbA1c (β = 0.46; 95% CI: 0.06, 0.85; P = 0.02). Only 2 studies examined folate supplementation on risk of T2D, and they found no change in RR (pooled RR: 0.91; 95% CI: 0.80, 1.04; P = 0.16). Conclusion Folate supplementation might be beneficial for glucose homeostasis and lowering IR, but at present there are insufficient data to conclusively determine the effect on development of T2D. This trial was registered on the Prospero database as CRD42016048254.

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Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

Molecular Psychiatry ◽

10.1038/s41380-019-0605-z ◽

2019 ◽

Cited By ~ 3

Author(s):

Tianye Jia ◽

Congying Chu ◽

Yun Liu ◽

Jenny van Dongen ◽

Evangelos Papastergios ◽

...

Keyword(s):

Dna Methylation ◽

Nucleus Accumbens ◽

Large Scale ◽

Biomarker Discovery ◽

Association Studies ◽

Meta Analysis ◽

Hippocampal Volume ◽

Small Sample ◽

Small Sample Sizes ◽

Meta Analyses

AbstractDNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

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P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors

Neuro-Oncology ◽

10.1093/neuonc/noz126.236 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii65-iii66

Author(s):

M Q S Mosella ◽

T S Sabedot ◽

T M Malta ◽

J Rock ◽

M Felicella ◽

...

Keyword(s):

Dna Methylation ◽

Target Genes ◽

Meta Analysis ◽

Differentially Expressed Gene ◽

Cell Movement ◽

Pituitary Tumors ◽

P Value ◽

Regulatory Regions ◽

Cpg Sites ◽

Invasive Behavior

Abstract BACKGROUND Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear. MATERIAL AND METHODS In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion. RESULTS Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05). CONCLUSION Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.

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A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms221910389 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10389

Author(s):

Negar Hosseinkhani ◽

Mahdi Abdoli Shadbad ◽

Mohammad Asghari Jafarabadi ◽

Noora Karim Ahangar ◽

Zahra Asadzadeh ◽

...

Keyword(s):

Systematic Review ◽

T Cells ◽

Cd8 T Cells ◽

Meta Analysis ◽

Strong Association ◽

Positive Association ◽

P Value ◽

Immune Resistance ◽

Current Systematic Review ◽

Meta Analyses

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11–1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43–3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36–2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10–2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

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Junk Food Consumption and Symptoms of Mental Health Problems: A Meta-Analysis for Public Health Awareness

Kesmas National Public Health Journal ◽

10.21109/kesmas.v16i1.4541 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Muhammad Hafizurrachman ◽

Risky Kusuma Hartono

Keyword(s):

Mental Health ◽

Mental Illness ◽

Food Consumption ◽

Mental Health Problems ◽

Meta Analysis ◽

Health Problems ◽

P Value ◽

Junk Food ◽

Frequent Consumption ◽

Meta Analyses

Junk food consumption increases the risk of having symptoms of mental health problems. This study aimed to conduct a meta-analysis to assess the association between junk food and symptoms of mental health problems. Six researchers, two primary researchers, and four assistant researchers, from October to December 2020 conducted a systematic literature review. The data sources were selected from Pubmed and Science Direct articles published from 2010 to 2020. Those websites were check-marked for text availability for original articles, using keywords for junk foods and mental health. This study had inclusion criteria for selecting and organizing articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The full-text articles were selected for conducting a meta-analysis using R Studio Software. The 5,079 article titles were obtained, seven of which met the relevant requirements for meta-analysis. The range of respondents who experienced symptoms of mental illness was 1.38%–79.8%. There was no heterogeneity based on the Tau-square test. The correlation coefficient was 0.11 (95% CI 0.09–0.14), with no publication bias based on Egger’s Regression test (0.6023 or p-value>0.05). The frequent consumption of junk food can contribute to mental illness symptoms, even with minimal effects.

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Anticariogenic action and safety profile of a cacao bean husk extract: A systematic review and meta-analysis

GSC Advanced Research and Reviews ◽

10.30574/gscarr.2021.8.1.0148 ◽

2021 ◽

Vol 8 (1) ◽

pp. 118-127

Author(s):

Flavio Martinez-Morales ◽

Saray Aranda Romo ◽

Othoniel Hugo Aragon-Martinez

Keyword(s):

Systematic Review ◽

Safety Profile ◽

Meta Analysis ◽

P Value ◽

Mouth Rinse ◽

P Values ◽

Scientific Databases ◽

Z Value ◽

Cariogenic Bacterium ◽

Meta Analyses

Nowadays, there is not a meta-analytic synthesis of the clinical reports that used a cacao bean husk extract (CBHE) solution as an anticariogenic mouth rinse. Thus, the aim of this study was to evaluate that information through a systematic review and meta-analysis methodology, conducted in accordance with PRISMA guidelines. Scientific databases were searched for studies published up to June 2021. Inclusion and exclusion criteria were applied to studies found and then, their data was analyzed. The five selected studies were categorized with a 36.6, 58.5, and 4.9 % of a low, unclear, and high risk of bias, respectively. Under appropriate heterogeneities (I2 values from 0 to 65 %, p values > 0.09) and absent reporting bias (symmetrical funnels), the meta-analyses show that the use of a CBHE mouth rinse reduced the salivary count of Streptococcus mutans (Z values from 2.45 to 10.61, p values < 0.01), similar to the chlorhexidine rinse performance (Z value= 0.55, p value= 0.58), and produced an insignificant presence of adverse events (Z value= 0.92, p value= 0.36) in children and adults, all these effects compared with those volunteers under an ethanol rinse or their pretest conditions. In conclusion, the CBHE mouth rinse reduced a cariogenic bacterium under an acceptable safety profile, but more clinical studies with high quality and more parameters are needed.

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Mortality rates in matched cohort, pseudo-randomised and randomised trials of convalescent plasma given to COVID-19 patients

10.1101/2020.11.19.20234757 ◽

2020 ◽

Author(s):

Amar Ahmad ◽

Marwa Salsabil ◽

Tim Oliver

Keyword(s):

Vitamin D ◽

Meta Analysis ◽

P Value ◽

Matched Cohort ◽

Randomised Trials ◽

Published Evidence ◽

Increased Risk ◽

Life Threatening ◽

Number Of Publications ◽

Meta Analyses

AbstractIntroductionFor more than 80 years convalescent or immune sera has been used in severe life threatening infections. Since March of this year a rapidly increasing number of publications have reported series of Convalescent plasma (CP) investigations in severely ill COVID-19 patients.Objectivea brief CP scoping review focusing on early mortalityMethodsWe searched available data bases. Three randomised trials, two pseudo-randomised observations and twelve matched cohort studies were identified. Random-effects meta-analyses were performed on extracted dataResultsA total of 2,378 CP treated and 5188 “controls” in 17 studies. Individually only two studies were significant for reduction of deaths to 30 days, but all showed a similar percentage reduction. When pooled, meta-analysis was undertaken. It showed that the overall reduction of death was significant for all series RR 0.710 (p=0.00001), all matched cohort series RR = 0.610 (p-value = 0.001) and the two pseudo-randomised series RR 0.747 (p=0.005) but not the three technically inadequate randomised trials, RR 0.825 (p=0.397). In two of these randomised trials, there was faster clearance of Viral DNA at 72 hours after CP than placeboConclusionIt is hoped the significance of this less than perfect data will increase interest in completing the delayed randomised trials as the results suggest they could be better than currently licenced drugs. Given increasing published evidence of increased risk of both diagnosis and death from COVID-19 in patients with severe Vitamin-D deficiency, future studies should also study influence of Vitamin-D status of donor and recipient on outcome.

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Survival Rate and Prosthetic and Sinus Complications of Zygomatic Dental Implants for the Rehabilitation of the Atrophic Edentulous Maxilla: A Systematic Review and Meta-Analysis

Biology ◽

10.3390/biology10070601 ◽

2021 ◽

Vol 10 (7) ◽

pp. 601

Author(s):

David Gutiérrez Muñoz ◽

Caterina Obrador Aldover ◽

Álvaro Zubizarreta-Macho ◽

Héctor González Menéndez ◽

Juan Lorrio Castro ◽

...

Keyword(s):

Systematic Review ◽

Survival Rate ◽

Dental Implants ◽

Clinical Studies ◽

Meta Analysis ◽

Case Series ◽

P Value ◽

High Survival ◽

Meta Analyses ◽

Prosthetic Complications

The aim of this systematic review and meta-analysis was to analyze and compare the survival rate and prosthetic and sinus complications of zygomatic dental implants for the rehabilitation of the atrophic edentulous maxilla. Materials and methods: We conducted a systematic literature review and meta-analysis, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of clinical studies that evaluated the survival rate and prosthetic and sinus complications of zygomatic dental implants for the rehabilitation of the atrophic edentulous maxilla. Four databases were consulted during the literature search: Pubmed–Medline, Scopus, Embase, and Web of Science. After eliminating duplicate articles and applying the inclusion criteria, 46 articles were selected for the qualitative analysis and 32 for the quantitative analysis. Results: Four randomized controlled trials, 19 prospective clinical studies, 20 retrospective studies, and 3 case series were included in the meta-analysis. Conventional dental implants failure (n = 3549) were seen in 2.89% (IC-95% 1.83–3.96%), while zygomatic dental implants failure (n = 1895) were seen in 0.69% (IC-95% 0.21–1.16%). The measure of the effect size used was the Odds Ratio, which was estimated at 2.05 with a confidence interval of 95% between 1.22 and 3.44 (z test = 2.73; p-value = 0.006). The failure risk of conventional dental implants is 2.1 times higher than that of zygomatic dental implants. Slight heterogeneity was determined in the meta-analysis between 23 combined studies (Q test = 32.4; p-value = 0.070; I2 = 32.1%). Prosthetic complications were recorded in 4.9% (IC-95% 2.7–7.3%) and mild heterogeneity was observed in a meta-analysis of 28 combined studies (Q test = 88.2; p-value = 0.001; I2 = 69.4%). Sinus complications were seen in 4.7% (IC-95% 2.8–6.5%) and mild heterogeneity was observed in a meta-analysis of 32 combined studies (Q test = 75.3; p-value = 0.001; I2 = 58.8%). Conclusions: The high survival rate and low prosthetic and sinus complications related to zygomatic dental implants suggest the use of zygomatic dental implants for the rehabilitation of the atrophic edentulous maxilla.

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Undernutrition and its determinants among Ethiopian adolescent girls: a protocol for systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2018-026718 ◽

2019 ◽

Vol 9 (5) ◽

pp. e026718 ◽

Cited By ~ 1

Author(s):

Wubet Worku Takele ◽

Achenef Asmamaw Muche ◽

Zeleke Abebaw Mekonnen ◽

Yehualashet Fikadu Ambaw ◽

Fasil Wagnew

Keyword(s):

Systematic Review ◽

Adolescent Girls ◽

Meta Analysis ◽

Health Concern ◽

Forest Plot ◽

P Value ◽

Pooled Prevalence ◽

Registration Number ◽

Trim And Fill ◽

Meta Analyses

IntroductionIn Ethiopia, undernutrition is the common public health concern, swaying the lives of lots of adolescent girls. Its sequelae are not only limited to them, but rather their upcoming offspring are vulnerable too. Even though some studies have been carried out in different parts of the country, the national pooled prevalence and determinants of undernutrition are not known. Therefore, this study is aimed at determining the pooled prevalence and determinants of undernutrition among adolescent girls in Ethiopia.MethodsPublished articles will be retrieved from databases such as Medline and PubMed. Electronic search engines such as Google Scholar and Google will be used. To identify eligible studies, the Joanna Briggs Institute quality appraisal checklists prepared for different study designs will be used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be used to maintain the scientific robustness of the study. The presence of heterogeneity among studies will be examined by forest plot as well as I2heterogeneity test. Potential causes of heterogeneity will be explored by carrying out sensitivity and subgroup analyses. The DerSimonian and Laird random-effects model will be used provided that heterogeneity is observed. Publication bias will be examined by observing funnel plots, and objectively by Egger’s regression test. If the funnel plot is asymmetric and/or Egger’s test was found to be statistically significant (p<0.05), the trim and fill (Duval and Tweedie’s) analysis will be performed. The presence of a statistical association between independent and dependent variables will be declared if the p value is <0.05 with the 95% CI.Ethics and disseminationSince this is a systematic review and meta-analysis, ethical clearance will not be a concern. The results of the study will be published in a peer-reviewed reputable journal and presented at different scientific research conferences.Trial registration numberCRD42018106180.

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