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1.
Insight into susceptibility genes associated with bipolar disorder: a systematic review.
Kalcev, G, Preti, A, Scano, A, Orrù, G, Carta, MG
European review for medical and pharmacological sciences. 2021;(18):5701-5724
Abstract
OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
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Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes.
Bozack, AK, Boileau, P, Wei, L, Hubbard, AE, Sillé, FCM, Ferreccio, C, Acevedo, J, Hou, L, Ilievski, V, Steinmaus, CM, et al
Environmental health : a global access science source. 2021;(1):79
Abstract
BACKGROUND Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS. METHODS DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs. RESULTS In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate. CONCLUSIONS Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.
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A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.
Jhun, MA, Mendelson, M, Wilson, R, Gondalia, R, Joehanes, R, Salfati, E, Zhao, X, Braun, KVE, Do, AN, Hedman, ÅK, et al
Nature communications. 2021;(1):3987
Abstract
Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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Effects of bariatric surgery on DNA methylation in adults: a systematic review and meta-analysis.
ElGendy, K, Malcomson, FC, Bradburn, DM, Mathers, JC
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2020;(1):128-136
Abstract
BACKGROUND DNA methylation is an epigenetic mechanism through which environmental factors, including obesity, influence health. Obesity is a major modifiable risk factor for many common diseases, including cardiovascular diseases and cancer. Obesity-induced metabolic stress and inflammation are key mechanisms that affect disease risk and that may result from changes in methylation of metabolic and inflammatory genes. OBJECTIVES This review aims to report the effects of weight loss induced by bariatric surgery (BS) on DNA methylation in adults with obesity focusing on changes in metabolic and inflammatory genes. METHODS A systematic review was performed using MEDLINE, EMBASE, and Scopus, to identify studies in adult humans that reported DNA methylation after BS. RESULTS Of 15,996 screened titles, 15 intervention studies were identified, all of which reported significantly lower body mass index postsurgery. DNA methylation was assessed in 5 different tissues (blood = 7 studies, adipose tissues = 4, skeletal muscle = 2, liver, and spermatozoa). Twelve studies reported significant changes in DNA methylation after BS. Meta-analysis showed that BS increased methylation of PDK4 loci in skeletal muscle and blood in 2 studies, while the effects of BS on IL6 methylation levels in blood were inconsistent. BS had no overall effect on LINE1 or PPARGC1 methylation. CONCLUSION The current evidence supports the reversibility of DNA methylation at specific loci in response to BS-induced weight loss. These changes are consistent with improved metabolic and inflammatory profiles of patients after BS. However, the evidence regarding the effects of BS on DNA methylation in humans is limited and inconsistent, which makes it difficult to combine and compare data across studies.
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Use of decitabine for patients with refractory or relapsed acute myeloid leukemia: a systematic review and meta-analysis.
Ma, YY, Zhao, M, Liu, Y, Zhao, DF, Wang, LX, Chen, XP, Li, L
Hematology (Amsterdam, Netherlands). 2019;(1):507-515
Abstract
Background: Approximately, one-third of adult patients with acute myeloid leukemia (AML) are refractory to initial induction chemotherapy and relapse occurs in most patients who achieve remission. This study evaluates the efficacy of decitabine in the management of refractory or relapsed AML. Methods: After literature search in electronic databases (Google Scholar, Embase, Ovid, and PubMed) studies were selected by following pre-determined eligibility criteria. Random-effects meta-analyses were performed to achieve effect sizes of complete remission (CR) rate, response rate (RR), and median survival after therapy. Subgroup analyses were performed with regards to use of decitabine with either epigenetics-based therapy, molecular therapy or chemotherapy. Results: Twenty studies were included (310 patients; age 55.1 years [95% confidence interval (CI): 43.8, 66.4]; 57% [52%, 63%] males). Overall RR was 46.1% [95% CI: 36.1%, 56.1%]. Overall CR rate was 23.5% [95% CI: 22.1%, 24.9%] but was 14.85% [95% CI: 3.8%, 25.9%] for decitabine with epigenetics-based therapies, 15.4% [95% CI: 6.7%, 24.0%] for decitabine with immunotherapy or molecular therapy, 34.8% [95% CI: 18.7%, 50.9%] for decitabine with chemotherapy, and 37.5% [36.4%, 38.7%] for decitabine with chemotherapy and molecular therapy. Median survival was 7.2 months [95% CI: 5.17, 9.3]. Major adverse events were neutropenia, nausea/vomiting, infections, fatigue, febrile neutropenia, diarrhea, thrombocytopenia, anemia, anorexia, leukopenia, hemorrhage, and hyperglycemia. Conclusion: Decitabine in combination with chemotherapy or molecular therapy has shown efficacious properties in refractory or relapsed AML patients.
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Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.
Gruzieva, O, Xu, CJ, Yousefi, P, Relton, C, Merid, SK, Breton, CV, Gao, L, Volk, HE, Feinberg, JI, Ladd-Acosta, C, et al
Environmental health perspectives. 2019;(5):57012
Abstract
BACKGROUND Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.
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7.
Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.
Agha, G, Mendelson, MM, Ward-Caviness, CK, Joehanes, R, Huan, T, Gondalia, R, Salfati, E, Brody, JA, Fiorito, G, Bressler, J, et al
Circulation. 2019;(8):645-657
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Abstract
BACKGROUND DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
Richard, MA, Huan, T, Ligthart, S, Gondalia, R, Jhun, MA, Brody, JA, Irvin, MR, Marioni, R, Shen, J, Tsai, PC, et al
American journal of human genetics. 2017;(6):888-902
Abstract
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
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The association between RARβ and FHIT promoter methylation and the carcinogenesis of patients with cervical carcinoma: A meta-analysis.
Shu, R, He, J, Wu, C, Gao, J
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2017;(6):1010428317709126
Abstract
The RARβ and FHIT promoter methylation are observed in some cervical carcinoma. However, the association between RARβ and FHIT promoter methylation and cervical carcinogenesis remains unclear. This study was carried out to evaluate the correlation between RARβ or FHIT promoter methylation and cervical carcinogenesis. Eligible publications were searched via online databases. The combined odds ratios and corresponding 95% confidence intervals were calculated and summarized. In all, 17 eligible articles on RARβ and FHIT promoter methylation were identified in the study. RARβ promoter methylation was significantly higher in cervical cancer than in cervical intraepithelial neoplasia lesions and normal cervical tissues (odds ratio = 3.90, p = 0.018; odds ratio = 12.98, p < 0.001, respectively). There was more FHIT promoter methylation in cervical cancer than in cervical intraepithelial neoplasia lesions and normal controls (odds ratio = 8.0, p = 0.055; odds ratio = 10.75, p < 0.001, respectively). In addition, FHIT promoter methylation was correlated with clinical stage (advanced stage vs early stage: odds ratio = 2.69, p = 0.056) and tumor grade (high grade vs low grade: odds ratio = 4.11, p < 0.001). RARβ and FHIT promoter methylation may be associated with the carcinogenesis of cervical cancer. FHIT promoter methylation may play a crucial role in cervical cancer progression. Additional studies with large sample sizes are essential to confirm our findings.
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Coffee consumption is associated with DNA methylation levels of human blood.
Chuang, YH, Quach, A, Absher, D, Assimes, T, Horvath, S, Ritz, B
European journal of human genetics : EJHG. 2017;(5):608-616
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Abstract
Beneficial health effects have been attributed to coffee consumption, but it is not yet known whether epigenetics may have a role in this process. Here we associate epigenome-wide DNA methylation levels to habitual coffee consumption from two studies with blood (2100 and 215 participants), and one with saliva samples (256 participants). Adjusting for age, gender, and blood cell composition, one CpG (cg21566642 near ALPPL2) surpassed genome-wide significance (P=3.7 × 10-10) and from among 10 additional CpGs significant at P≤5.0 × 10-6, six were located within 1500 bps of a transcriptional start site. Results for these 11 top-ranked CpGs remained significant after further adjusting for smoking. Also, methylation levels of another 135 CpGs were influenced by both coffee drinking and smoking (P≤1.0 × 10-7). Functional enrichment analysis suggested that coffee-associated CpGs were located near transcription factor binding (P=1.2 × 10-6) and protein kinase activity genes (P=2.9 × 10-5). Interestingly, when we stratified by menopausal hormone therapy (MHT), methylation differences with coffee consumption were observed only in women who never used MHT. We did not replicate any of the associations found in blood in our saliva samples, suggesting that coffee may affect DNA methylation levels in immune cells of the blood but not in saliva.