Prenatal famine exposure, health in later life and promoter methylation of four candidate genes

2012 ◽  
Vol 3 (6) ◽  
pp. 450-457 ◽  
Author(s):  
M. V. Veenendaal ◽  
P. M. Costello ◽  
K. A. Lillycrop ◽  
S. R. de Rooij ◽  
J. A. van der Post ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Promoter Methylation ◽  
Peripheral Blood ◽  
Methylation Status ◽  
Later Life ◽  
Proximal Promoter ◽  
Promoter Regions ◽  
Increased Risk ◽  
Famine Exposure ◽  
Prenatal Famine

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944–45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

The Relationship Between P16INK4A and TP53 Promoter Methylation and The Risk and Prognosis in Patients With Oesophageal Cancer in Thailand

2021 ◽  
Author(s):  
Arisara Poosari ◽  
Thitima Nutravong ◽  
Wises Namwat ◽  
Wiphawan Wasenang ◽  
Prakasit Sa-ngiamwibool ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Oesophageal Cancer ◽  
Promoter Methylation ◽  
Cox Regression ◽  
Methylation Status ◽  
Predictive Biomarker ◽  
Study Data ◽  
Tumour Suppressor Genes ◽  
Promoter Methylation Status ◽  
Increased Risk

Abstract DNA methylation can regulate the expression of tumour suppressor genes P16 and TP53, environmental factors, which are both important factors related to an increased risk and prognosis of oesophageal cancer (EC). However, the association between these two genes methylation status, as well as the effects of gene-environment interactions, EC risk remains unclear. A Hospital-based case-control study data were collected from 105 new EC cases and 108 controls. Promoter methylation status was investigated for P16 and TP53 genes using methylation-specific polymerase (MSP) chain reaction methods with SYBR green. Logistic and Cox regression models were used to analyse the association of P16 and TP53 promotor methylation status with EC risk and prognosis, respectively. Our results suggest P16, TP53 methylation significantly increased the risk of EC (OR = 5.24, 95 % CI: 2.57–10.66, P < 0.001; OR = 3.38, 95% CI: 1.17–6.67, P < 0.001, respectively). In addition, P16 and TP53 promoter methylation status and the combined effects between environmental factors and its methylations in tissue were correlated with the EC risk and prognosis of EC patients. As a new biomarker, the methylation of P16 and TP53 can serve as a potential predictive biomarker of EC.

Low THRB (thyroid hormone receptor beta) Promoter Methylation Levels in Peripheral Blood Leukocytes Induced By Systematic Inflammation Are Involved in Low Thyroid Hormone Function in Metabolic Syndrome

Hypertension ◽  
2021 ◽  
Author(s):  
Bing Cui ◽  
Xiao Xiao ◽  
Jin’e Wang ◽  
Hongrui Wang ◽  
Cunjin Wu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Thyroid Hormone ◽  
Promoter Methylation ◽  
Peripheral Blood ◽  
Thyroid Hormone Receptor ◽  
Oral Treatment ◽  
Methylation Status ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
A Genome

Abnormal thyroid hormone (TH) function has been observed in all components of metabolic syndrome (MetS), but the mechanisms remain unclear. Altered genomic methylation status is closely related to MetS. Our aim was to determine whether methylation regulation in TH function–related genes is involved in MetS. In a small strictly selected cohort, low TH function was observed in MetS group, as well as lower THRB promoter methylation levels in peripheral blood leukocytes in a genome-wide methylation screening by Illumina 450K beadchip. The results of beadchip assay were then confirmed by Sequenom MassARRAY. Low THRB promoter methylation levels and low TH function in MetS were confirmed in another big-size validation cohort. Lower methylation levels were associated with higher THRB expression in peripheral blood leukocytes, and altered THRB promoter methylation status influenced its promoter activity and expression. In the MetS rat models constructed by high fat and high fructose diet, lower TH function was also observed, as well as lower Thrb promoter methylation levels. Furthermore, systematic inflammation observed in MetS was found to induce decreased THRB promoter methylation levels as well as corresponding THRB expression. Additionally, oral treatment with a physiological T3 dose mitigated hypertension and insulin resistance and partially alleviated hepatic steatosis and adipocyte hypertrophy in MetS rats. Low methylation levels of THRB promoter in peripheral blood leukocytes induced by systematic inflammation were involved in low TH function in MetS, whereas low TH function deteriorates MetS. This might serve as a novel therapeutic target of MetS.

scholarly journals Bisphenol a Exposure, DNA Methylation, and Asthma in Children

2020 ◽  
Vol 17 (1) ◽  
pp. 298 ◽  
Author(s):  
Chia-Feng Yang ◽  
Wilfried J. J. Karmaus ◽  
Chen-Chang Yang ◽  
Mei-Lien Chen ◽  
I-Jen Wang
Keyword(s):  
Dna Methylation ◽  
Bisphenol A ◽  
Candidate Genes ◽  
Promoter Methylation ◽  
Childhood Asthma ◽  
Methylation Status ◽  
Differential Methylation ◽  
Study Cohort ◽  
Blood Samples ◽  
Asthma In Children

Epidemiological studies have reported the relationship between bisphenol A (BPA) exposure and increased prevalence of asthma, but the mechanisms remain unclear. Here, we investigated whether BPA exposure and DNA methylation related to asthma in children. We collected urinary and blood samples from 228 children (Childhood Environment and Allergic Diseases Study cohort) aged 3 years. Thirty-three candidate genes potentially interacting with BPA exposure were selected from a toxicogenomics database. DNA methylation was measured in 22 blood samples with top-high and bottom-low exposures of BPA. Candidate genes with differential methylation levels were validated by qPCR and promoter associated CpG islands have been investigated. Correlations between the methylation percentage and BPA exposure and asthma were analyzed. According to our findings, MAPK1 showed differential methylation and was further investigated in 228 children. Adjusting for confounders, urinary BPA glucuronide (BPAG) level inversely correlated with MAPK1 promoter methylation (β = −0.539, p = 0.010). For the logistic regression analysis, MAPK1 methylation status was dichotomized into higher methylated and lower methylated groups with cut off continuous variable of median of promoter methylation percentage (50%) while performing the analysis. MAPK1 methylation was lower in children with asthma than in children without asthma (mean ± SD; 69.82 ± 5.88% vs. 79.82 ± 5.56%) (p = 0.001). Mediation analysis suggested that MAPK1 methylation acts as a mediation variable between BPA exposure and asthma. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation.

Promoter Methylation and Decreased Expression of Mir-124 In Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4014-4014
Author(s):  
Yuesheng Meng ◽  
Qiao Xia ◽  
Jun Hu
Keyword(s):  
Myelodysplastic Syndromes ◽  
Promoter Methylation ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Methylation Status ◽  
Polymerase Chain Reaction Analysis ◽  
Promoter Regions ◽  
Hematopoietic Stem

Abstract Abstract 4014 The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic stem/progenitor cells. Although demethylating agents such azacytidine and decitabine have been widely used to treat MDS, the underlying molecular mechanisms remain obscure. Abnormalities of microRNAs (miRNA) have been recently associated with hematological malignancies including MDS. The miR-124 was initially demonstrated to modulate neurogenesis. It was recently shown that EVI1-induced methylation and silencing of miR-124 were present in murine MDS cells. In the retrospective study we evaluated methylation status and expression levels of miR-124 in fifteen MDS patients (subtypes included RCUD, RCMD, RAEB-1, RAEB-2 and CMML). Genomic DNA samples were modified with bisulfite and methylation at three promoter regions of miR-124 was examined with methylation-specific real time quantitative polymerase chain reaction analysis (MQPCR). In general, we observed an increased methylation levels of miR-124 in MDS patients than that in normal bone marrow (NBM, P<0.01). In accordance with this, marked depression of miR-124 was seen in six patients when compared with NBM (more than 2 times lower), as determined with quantitative reverse-transcriptive PCR assay. Moreover, there were higher degrees of promoter methylation in cases with depressed miR-124 than that in remaining cases. A negative correlation between the expression and methylation levels was statistically significant (R= -0.498, P<0.01). The change of miR-124 was not directly related to short-term clinical response or prognosis, possibly due to limited size of the sample. However, the miR-124 amount returned to basal levels in two cases (RCMD and CMML subtypes respectively) after low-dose decitabine therapy and DNA methylation of all three loci disappeared. Continued work is underway to accumulate more cases and make long-term clinical follow-up. In conclusion, this primary work suggested a possible role of the methylation-mediated silencing of miR-124 in the pathogenesis or disease progression of MDS. Disclosures: No relevant conflicts of interest to declare.

Title: Promoter Methylation of Selected Genes and Response to Azacitidine (AZ) Therapy in Patients with Non-BCR-ABL Myeloproliferative Disorders (MPDs)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4625-4625
Author(s):  
Nicholas Achille ◽  
Laura Michaelis ◽  
Scott E. Smith ◽  
Eliza Germano ◽  
Nancy J. Zeleznik-Le ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Research Funding ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Cpg Islands ◽  
Myeloproliferative Disorders ◽  
Response To Treatment ◽  
Promoter Regions ◽  
Days Of Therapy

Abstract Abstract 4625 Background: Gene silencing via methylation of CpG islands in the promoter regions of many genes but specifically of APAF1, p15INK4B, p16INK4A, RARB, and CDH1 appears to play a role in pathogenesis of myeloid malignancies. Azacitidine (AZ) causes demethylation by inhibiting DNA methyltransferase and has already been shown to be an effective therapy for myelodysplastic syndromes. The demethylation induced by AZ is detectable in about 48 hours and increases significantly after 5 days of therapy. After that, the effect tends to plateau. Methods: We initiated a Phase 2 study of patients with non-BCR-ABL MPDs to determine clinical response to AZ therapy and correlate it with promoter DNA methylation and gene re-expression. The protocol was approved by the institutional IRB. Patients received AZ 75mg/m2 s/c for days 1–7 and repeated every 28 days for a minimum of 4 cycles. Responders were allowed to continue treatment until disease progression. Pretreatment and D 7 peripheral blood samples were analyzed for promoter methylation status and expression of the 5 genes mentioned above. Bisulfite conversion of DNA was followed by quantitative PCR using primers specific for methylated or for unmethylated promoter regions. For gene re-expression analysis, quantitative RT-PCR was performed with RNA isolated from the same patient samples and the same time points as the DNA methylation analyses. Results: Seven patients were enrolled before the study closed due to lack of accrual. The diagnoses were: Myelofibrosis (MF) 4, essential thrombocythemia 1, unclassified MPD with dysplasia 2. One patient with MF and one with unclassified MPD responded, the latter with normalization of marrow karyotype. Both responses were accompanied by significant decrease in APAF1 promoter methylation and surprisingly, an increase in promoter methylation of RARB. In three of the non-responders, APAF1 methylation increased. In patients with decreased Apaf1 methylation, a statistically significant increase in mRNA expression was observed. Conclusions: Within its limitations, this small trial shows that the methylation status of selected genes, particularly of APAF1 and RARB (inversely) is associated with response to treatment with azacitidine in patients with MPDs. In non-responders, Apaf1 methylation appears to increase. A larger study will be necessary to confirm these preliminary observations. Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Nand:Celgene Corporation: Research Funding.

scholarly journals Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene

2011 ◽  
Vol 106 (5) ◽  
pp. 769-778 ◽  
Author(s):  
M. Palou ◽  
Catalina Picó ◽  
J. A. McKay ◽  
J. Sánchez ◽  
T. Priego ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Leptin Receptor ◽  
Methylation Status ◽  
Male Rats ◽  
Mrna Levels ◽  
Protective Effects ◽  
Suckling Period ◽  
Promoter Regions ◽  
Weak Negative Correlation ◽  
Physiological Dose

Leptin supplementation of neonatal rats during the suckling period protects against being overweight in adulthood and ameliorates the control of food intake. This was associated with changes in the expression of hypothalamic genes involved in the central action of leptin: pro-opiomelanocortin (Pomc), leptin receptor (Lepr) and suppressor of cytokine signalling (Socs3). The purpose of the present study was to determine the methylation status within the promoter regions of these genes and to assess whether the observed changes in the expression levels of these genes could be explained by changes in their methylation status. Male rats were treated daily with an oral physiological dose of leptin or vehicle during the suckling period. After weaning, animals were fed with a normal-fat or a high-fat (HF) diet until aged 6 months. DNA was extracted from the hypothalamus and methylation within the promoter regions of the gene panel was measured by pyrosequencing. Pomc promoter methylation increased in control animals fed the HF diet but decreased in leptin-treated animals. In addition, there was a weak negative correlation between DNA methylation and POMC mRNA levels (P = 0·075). There were no changes in the methylation status of the CpG sites studied within the promoter regions of Lepr and Socs3 in response to leptin or HF treatments. This is the first demonstration that leptin treatment during lactation may programme methylation of an appetite-related gene in the hypothalamus of animals fed HF diets, with possible implications for gene expression and protection against the development of obesity.

scholarly journals Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients

2009 ◽  
Vol 27 (19) ◽  
pp. 3161-3168 ◽  
Author(s):  
Lorenzo Richiardi ◽  
Valentina Fiano ◽  
Loredana Vizzini ◽  
Laura De Marco ◽  
Luisa Delsedime ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Promoter Methylation ◽  
A Priori ◽  
Methylation Status ◽  
Specific Antigen ◽  
Prostate Cancer Progression ◽  
Increased Risk ◽  
In The Beginning

Purpose There is a need to better understand prostate cancer progression and identify new prognostic markers for this tumor. We investigated the association between promoter methylation in a priori selected genes and survival in two independent large series of prostate cancer patients. Methods We followed up with two cohorts of patients (216 patients diagnosed in 1982 to 1988 and 243 patients diagnosed in 1993 to 1996) diagnosed at one hospital pathology ward in Turin, Italy. DNA was obtained from paraffin-embedded tumor tissues and evaluated for promoter methylation status in glutathione S-transferase (GSTP1), adenomatous polyposis coli (APC), and runt-related transcription factor 3 (RUNX3). Results The two cohorts had different prevalences of methylation in APC (P = .047), GSTP1 (P = .002), and RUNX3 (P < .001). Methylation in APC was associated with an increased risk of prostate cancer–specific mortality (hazard ratio [HR] = 1.42; 95% CI, 0.98 to 2.07 in the 1980s cohort; HR = 1.57; 95% CI, 0.95 to 2.62 in the 1990s cohort; HR = 1.49; 95% CI, 1.11 to 2.00 in the two cohorts combined). In subgroup analyses, the HRs were higher among patients with a Gleason score less than 8 (HR = 1.52; 95% CI, 0.85 to 2.73 in the 1980s cohort; HR = 2.09; 95% CI, 1.02 to 4.28 in the 1990s cohort). Methylation in RUNX3 was associated with prostate cancer mortality only in the 1990s cohort, and methylation in GSTP1 did not predict mortality in either cohort. Conclusion The pattern of hypermethylation may have changed after the introduction of prostate-specific antigen testing in the beginning of the 1990s. Promoter methylation in APC was identified as a marker for prostate cancer progression.

Analysis of Promoter Methylation, Polymorphism and Expression Prole of Cytotoxic T-Lymphocyte-Associated Antigen-4 in Patients with Gastric Cancer

2014 ◽  
Vol 23 (3) ◽  
pp. 249-253 ◽  
Author(s):  
Dor Mohammad Kordi-Tamandani ◽  
Shahrbbanou Karimi Davani ◽  
Taybeh Baranzehi ◽  
Simin Hemati
Keyword(s):  
Gastric Cancer ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Promoter Methylation ◽  
Cytotoxic T Lymphocyte ◽  
Methylation Status ◽  
Cancer Tissue ◽  
Tissue Samples ◽  
Increased Risk ◽  
Ctla4 Gene

AbstractBackground & Aim: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) is a crucial immune-checkpoint receptor regulating T-cell activation. The current study was carried out to evaluate the function of CTLA4 gene in patients with gastric cancer.Methods: The methylation of CTLA4 gene promoter was evaluated by methylation-specific polymerase chain reaction (MSP) technique using 85 paraffin-embedded gastric cancer tissue samples and normal tissue on the tumor margins as control tissue samples. Expression analysis was performed on paraffin-embedded tissue samples (25 each of cancerous and normal tissues) using Real-time PCR.Results: Statistically significant differences were observed between the tumor and margin-cell areas withrespect to promoter methylation status (OR = 4.829, 95% CI: 2.46-9.48, p < 0.001) and CTLA4 expression profile (mean ± SD = 7.56 ± 17.35, p = 0.04).Conclusion: To the best of our knowledge, the current study is the first one highlighting the association between promoter hypermethylation of CTLA4 gene, decreased CTLA4 expression, and increased risk of gastric cancer.

Association between the Great China Famine exposure in early life and risk of arthritis in adulthood

2018 ◽  
Vol 72 (9) ◽  
pp. 790-795 ◽  
Author(s):  
Zhenghe Wang ◽  
Zhiyong Zou ◽  
Bin Dong ◽  
Jun Ma ◽  
Luke Arnold
Keyword(s):  
Early Life ◽  
Weight Control ◽  
Later Life ◽  
Elevated Risk ◽  
Exposed Group ◽  
Nutrition Intervention ◽  
Control Group ◽  
Increased Risk ◽  
Famine Exposure ◽  
Stratified Analysis

BackgroundThe association between famine exposure in early life and risk of arthritis (combination of osteoarthritis and inflammatory arthritis) in adulthood is unclear. The aim of this study is to explore the association.MethodsA total of 4124 subjects were selected from the national data of the China Health and Retirement Longitudinal Study in 2011–2012. Doctor-diagnosed arthritis was self-reported in participants’ questionnaire. Birthdates were used to categorise participants into famine-exposed and non-exposed groups. Logistic regression model was used to explore the association of famine exposure in early life with the risk of arthritis in adulthood.ResultsThe prevalence of arthritis in both infant-exposed and preschool-exposed groups was significantly higher than those in the non-exposed group (35.0% and 30.6% vs 27.3%; p<0.05). Compared with the non-exposed group, the infant-exposed group showed a significantly elevated risk of arthritis in adulthood after adjusting for confounding factors (OR=1.65; 95% CI 1.29 to 2.11; p<0.001). In the stratified analysis, we found that participants who lived in severely affected areas (OR=1.91; 95% CI 1.41 to 2.59; p<0.001), who are female (OR=2.21; 95% CI 1.57 to 3.11; p<0.001) and those with a body mass index ≥24.0 kg/m2 (OR=2.46; 95% CI 1.70 to 3.55; p<0.001) in the infant-exposed group had increased risk of arthritis in adulthood. Similar results were additionally observed when age-balanced control group was used.ConclusionGreat China Famine exposure in infancy may be associated with an elevated risk of arthritis in adulthood, particularly in women and participants with adiposity. These findings suggest nutrition intervention in infancy and weight control in later life may reduce the risk of arthritis in adulthood.

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