Apolipoprotein E DNA methylation and late-life disease

Abstract Background This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimeŕs disease (AD) or cardiovascular disease (CVD). Methods DNA methylation across theAPOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3′exon that also harbours theAPOE ε2 and ε4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease. Results We found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08–1.62 for dementia; OR 1.38, 95% CI 1.07–1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function ofAPOE genotype. Conclusions We found that higher DNA methylation levels in the promoter region ofAPOE increase the odds of dementia and AD, but not CVD. The effect was independent ofAPOE genotype, indicating that allelic variation and methylation variation inAPOE may act independently to increase the risk of dementia.

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Agreement in DNA methylation levels from the Illumina 450K array across batches, tissues, and time

Epigenetics ◽

10.1080/15592294.2017.1411443 ◽

2018 ◽

Vol 13 (1) ◽

pp. 19-32 ◽

Cited By ~ 16

Author(s):

Marie Forest ◽

Kieran J. O'Donnell ◽

Greg Voisin ◽

Helene Gaudreau ◽

Julia L. MacIsaac ◽

...

Keyword(s):

Dna Methylation ◽

450K Array ◽

Illumina 450K ◽

Illumina 450K Array

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Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

10.1101/491845 ◽

2018 ◽

Author(s):

Shicai Fan ◽

Jianxiong Tang ◽

Nan Li ◽

Ying Zhao ◽

Rizi Ai ◽

...

Keyword(s):

Dna Methylation ◽

Human Genome ◽

Therapeutic Targets ◽

Integrative Analysis ◽

Axonal Guidance ◽

Methylation Data ◽

450K Array ◽

Diagnosis And Prognosis ◽

Illumina 450K ◽

Illumina 450K Array

AbstractThe integration of genomic and DNA methylation data has been demonstrated as a powerful strategy in understanding cancer mechanisms and identifying therapeutic targets. The TCGA consortium has mapped DNA methylation in thousands of cancer samples using Illumina Infinium Human Methylation 450K BeadChip (Illumina 450K array) that only covers about 1.5% of CpGs in the human genome. Therefore, increasing the coverage of the DNA methylome would significantly leverage the usage of the TCGA data. Here, we present a new model called EAGLING that can expand the Illumina 450K array data 18 times to cover about 30% of the CpGs in the human genome. We applied it to analyze 13 cancers in TCGA. By integrating the expanded methylation, gene expression and somatic mutation data, we identified the genes showing differential patterns in each of the 13 cancers. Many of the triple-evidenced genes identified in the majority of the cancers are biomarkers or potential biomarkers. Pan-cancer analysis also revealed the pathways in which the triple-evidenced genes are enriched, which include well known ones as well as new ones such as axonal guidance signaling pathway and pathways related to inflammatory processing or inflammation response. Triple-evidenced genes, particularly TNXB, RRM2, CELSR3, SLC16A3, FANCI, MMP9, MMP11, SIK1, TRIM59, showed superior predictive power in both tumor diagnosis and prognosis. These results have demonstrated that the integrative analysis using the expanded methylation data is powerful in identifying critical genes/pathways that may serve as new therapeutic targets.

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Faculty Opinions recommendation of Agreement in DNA methylation levels from the Illumina 450K array across batches, tissues, and time.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732585322.793542230 ◽

2018 ◽

Cited By ~ 1

Author(s):

John Holloway

Keyword(s):

Dna Methylation ◽

450K Array ◽

Illumina 450K ◽

Illumina 450K Array

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On the Analysis of the Illumina 450k Array Data: Probes Ambiguously Mapped to the Human Genome

Frontiers in Genetics ◽

10.3389/fgene.2012.00073 ◽

2012 ◽

Vol 3 ◽

Cited By ~ 12

Author(s):

Xu Zhang ◽

Wenbo Mu ◽

Wei Zhang

Keyword(s):

Human Genome ◽

450K Array ◽

Array Data ◽

Illumina 450K ◽

Illumina 450K Array

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Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array

Epigenetics & Chromatin ◽

10.1186/1756-8935-6-26 ◽

2013 ◽

Vol 6 (1) ◽

pp. 26 ◽

Cited By ~ 148

Author(s):

Roderick C Slieker ◽

Steffan D Bos ◽

Jelle J Goeman ◽

Judith VMG Bovée ◽

Rudolf P Talens ◽

...

Keyword(s):

Differentially Methylated Regions ◽

450K Array ◽

Tissue Specific ◽

Illumina 450K ◽

Illumina 450K Array

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EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4804 ◽

2008 ◽

Vol 31 (4) ◽

pp. 11

Author(s):

Manda Ghahremani ◽

Courtney W Hannah ◽

Maria Peneherrera ◽

Karla L Bretherick ◽

Margo R Fluker ◽

...

Keyword(s):

Dna Methylation ◽

Premature Ovarian Failure ◽

Promoter Region ◽

Gene Promoter ◽

Ovarian Failure ◽

P Value ◽

Epigenetic Alterations ◽

Methylation Array ◽

Cpg Sites ◽

Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

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Correlation of methylation status in MTHFR promoter region with recurrent pregnancy loss

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00147-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Mai Mahmoud Shaker ◽

Taghreed Abdelmoniem shalabi ◽

Khalda said Amr

Keyword(s):

Dna Methylation ◽

Dna Sequences ◽

Promoter Region ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Methylation Status ◽

Control Group ◽

Case Group ◽

Methyl Radical ◽

Fertile Women

Abstract Background DNA methylation is an epigenetic process for modifying transcription factors in various genes. Methylenetetrahydrofolate reductase (MTHFR) stimulates synthesis of methyl radical in the homocysteine cycle and delivers methyl groups needed in DNA methylation. Furthermore, numerous studies have linked gene polymorphisms of this enzyme with a larger risk of recurrent pregnancy loss (RPL), yet scarce information is available concerning the association between epigenetic deviations in this gene and RPL. Hypermethylation at precise DNA sequences can function as biomarkers for a diversity of diseases. We aimed by this study to evaluate the methylation status of the promoter region of MTHFR gene in women with RPL compared to healthy fertile women. It is a case–control study. Hundred RPL patients and hundred healthy fertile women with no history of RPL as controls were recruited. MTHFR C677T was assessed by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Quantitative evaluation of DNA methylation was performed by high-resolution melt analysis by real-time PCR. Results The median of percentage of MTHFR promoter methylation in RPL cases was 6.45 [0.74–100] vs. controls was 4.50 [0.60–91.7], P value < 0.001. In the case group, 57 hypermethylated and 43 normo-methylated among RPL patients vs. 40 hypermethylated and 60 normo-methylated among controls, P< 0.005. Frequency of T allele in C677T MTHFR gene among RPL patients was 29% vs. 23% among the control group; C allele vs. T allele: odds ratio (OR) = 1.367 (95% confidence interval (CI) 0.725–2.581). Conclusion Findings suggested a significant association between hypermethylation of the MTHFR promoter region in RPL patients compared to healthy fertile women.

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NRAMP1 Polymorphism and Viral Factors in Sardinian Multiple Sclerosis Patients

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100009173 ◽

2008 ◽

Vol 35 (4) ◽

pp. 491-494 ◽

Cited By ~ 12

Author(s):

Maria Gazouli ◽

Leonardo Sechi ◽

Daniela Paccagnini ◽

Stefano Sotgiu ◽

Giannina Arru ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Disease ◽

Promoter Region ◽

Viral Infections ◽

Jc Virus ◽

Allelic Variation ◽

Sardinian Population ◽

Multiple Sclerosis Patients ◽

Viral Sequences

Background:Multiple sclerosis (MS) is believed to be an autoimmune disease occurring in genetically predisposed individuals after an appropriate environmental exposure such as viral infections. Recent studies suggest a significant association between MS and the functional 5’-(GT)n polymorphism in the promoter region of the NRAMP1 gene. In the present study we aimed to evaluate the contribution of the allelic variation in the NRAMP1 promoter to MS susceptibility and to study the role of viral infection in relation to specific NRAMP1 genotypes, in a Sardinian cohort.Methods:Sixty MS patients and 66 healthy individuals were genotyped, and screened for the presence of Epstein-bar virus (EBV) and JC virus (JCV) sequences.Results:Consistent with previous autoimmune disease studies, allele 3 at the functional 5’(GT)n promoter region repeat polymorphism, was significantly overrepresented among MS patients when compared to controls (p=0.02). The EBV and JCV sequences were detected in 8/60 (13.33%) and in 4/60 (6.66%) of MS patients respectively and in 5/66 (7.57%) and in 0/66 of controls.Conclusion:The allelic variation in the NRAMP1 promoter may contribute to MS susceptibility in the Sardinian population. The viral sequences were not confined to a specific NRAMP1 genotype.

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Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer’s Disease

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-201000 ◽

2021 ◽

pp. 1-8

Author(s):

Natalia Bezuch ◽

Steven Bradburn ◽

Andrew C. Robinson ◽

Neil Pendleton ◽

Antony Payton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Fluid Intelligence ◽

Cpg Island ◽

Amyloid Β ◽

Superior Frontal Gyrus ◽

Protein Levels ◽

Apoe Protein ◽

Apoe Locus

Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

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