scholarly journals THU0004 GENOME-WIDE DNA METHYLATION PROFILING IN MONOCYTES FROM PRIMARY ANTIPHOSPHOLIPID SYNDROME PATIENTS IDENTIFIES AN ABERRANT METHYLATION SIGNATURE ASSOCIATED WITH THEIR ATHEROTHROMBOTIC PHENOTYPE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 214.2-215
Author(s):  
C. Perez-Sanchez ◽  
A. M. Patiño-Trives ◽  
M. A. Aguirre ◽  
P. S. Laura ◽  
M. Luque-Tévar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Methylation Profile ◽  
Aberrant Methylation ◽  
Functional Classification ◽  
Research Support ◽  
Genome Wide

Background:Recent studies underlined the crucial role of DNA methylation in several autoimmune diseases by altering gene expression profiles, thus influencing disease severity. Yet, aberrant methylation patterns in monocytes, key players in the pathogenesis of APS patients, has not been evaluated.Objectives:To analyze the genome-wide DNA methylation profile of monocytes from APS patients and its relationship with the cardiovascular (CV) pathology. 2. To evaluate the role of antiphospholipid antibodies (aPL) in the regulation of this process.Methods:Thirty-three APS patients and 15 healthy donors (HD) were included in the study. Monocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium Methylation EPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs (TSS1500, TSS200, 5UTR, 3UTR, first exon, intergenic, gene body). Beta values (β) estimating methylation levels were obtained at each CpG site, and differentially methylated genes (DMG) between APS and HD were identified. Functional classification of that genes was carried out by gene ontology analysis (PANTHER database). Gene expression of selected DMG genes was evaluated by RT-PCR. CV-risk parameters, including carotid intima-media thickness (CIMT) and microvascular endothelial function were further assessed, and correlation/association studies were developed with clinical and analytical variables. The effects of aPLs were also evaluated byin vitrostudies.Results:Genome-wide DNA methylation analysis identified 813 DMG, including 279 hypomethylated and 534 hypermethylated. Functional classification of these genes revealed signatures associated with biological processes and pathways related to their clinical profile, including immune response, adhesion, oxidative stress and vascular signaling. Correlation and association studies showed that the methylation levels of genes related to immune response were associated with the CV-risk score, aGAPSS (CCR2, TXLNB, GLIPR), type of thrombosis (SIGLEC11, COLEC11, LRRC16A, AHSA1, TRIL) and aPL titers (CLEC4G, RGS4, HLA-DPA1, GBP6, RAET1E, HLA-G, HLA-DPA1, HLA-H, TXLNB). Besides, methylation levels of DMG related to vascular signaling and adhesion processes were associated with the presence of thrombotic recurrences (VEGFA, MAPK14, ITGA8, EPCAM, PCDHA6, DLG1) as well as with traditional CV-risk factor such as hypertension and dyslipidemia (ITGA11, DSCAM, CLEC4F, CDH4, LTBP2, PCDHB14). In addition, methylation levels of DMG genes related to oxidative stress (GP2, PGD, ADH1) were associated with microvascular endothelial dysfunction. An altered mRNA expression of some of those genes with aberrant methylation and related to increased CV-risk and thrombotic recurrences in APS was also identified. Both, abnormal methylation and transcription levels of several genes were further associated with a pathological increase of the CIMT. Finally, in vitro studies supported the role of aPLs as key players in the altered methylation and transcriptomic profiles of APS patients.Conclusion:APS patients showed an impaired methylation profile in monocytes of genes associated with clinical features of the disease, including aPL titers, CV risk, thrombotic recurrences, endothelial dysfunction and early atherosclerosis. These results offered a map to the monocytes methylome and shed light on the pathophysiology of APS, paving the way for the development of new, more effective biomarkers and therapeutics.Acknowledgments:Funded by ISCIII (PI18/0837 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Carlos Perez-Sanchez: None declared, Alejandra M. Patiño-Trives: None declared, Maria A Aguirre: None declared, Pérez Sánchez Laura: None declared, María Luque-Tévar: None declared, Iván Arias de la Rosa: None declared, Carmen Torres-Granados: None declared, Maria del Carmen Abalos-Aguilera: None declared, Pedro Seguí Azpilcueta: None declared, Javier Rodríguez: None declared, Esteban Ballester: None declared, Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene., Eduardo Collantes Estevez Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene, Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer.

scholarly journals Genome-Wide Analysis of the DNA Methylation Profile Identifies the Fragile Histidine Triad (FHIT) Gene as a New Promising Biomarker of Crohn’s Disease

2020 ◽  
Vol 9 (5) ◽  
pp. 1338 ◽  
Author(s):  
Tae-Oh Kim ◽  
Dong-Il Park ◽  
Yu Kyeong Han ◽  
Keunsoo Kang ◽  
Sae-Gwang Park ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Methylation Profile ◽  
Fhit Gene ◽  
Genome Wide ◽  
Dna Methylation Profile ◽  
Inflammatory Bowel

Inflammatory bowel disease is known to be associated with a genetic predisposition involving multiple genes; however, there is growing evidence that abnormal interactions with environmental factors, particularly epigenetic factors, can also significantly contribute to the development of inflammatory bowel disease (IBD). Although many genome-wide association studies have been performed to identify the genetic changes underlying the pathogenesis of Crohn’s disease, the role of epigenetic alterations based on molecular complications arising from Crohn’s disease (CD) is poorly understood. We employed an unbiased approach to define DNA methylation alterations in colonoscopy samples from patients with CD using the HumanMethylation450K BeadChip platform. Technical and functional validation was performed by methylation-specific PCR (MSP) and bisulfite sequencing of a validation set of 207 patients with CD samples. Immunohistochemistry (IHC) analysis was performed in the representative sample sets. DNA methylation profile in CD revealed that 135 probes (24 hypermethylated and 111 hypomethylated probes) were differentially methylated. We validated the methylation levels of 19 genes that showed hypermethylation in patients with CD compared with normal controls. We uniquely identified that the fragile histidine triad (FHIT) gene was hypermethylated in a disease-specific manner and its protein level was downregulated in patients with CD. Pathway analysis of the hypermethylated candidates further suggested putative molecular interactions relevant to IBD pathology. Our data provide information on the biological and clinical implications of DNA hypermethylated genes in CD, identifying FHIT methylation as a promising new biomarker for CD. Further study of the role of FHIT in IBD pathogenesis may lead to the development of new therapeutic targets.

scholarly journals Alzheimer's disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

2021 ◽  
Author(s):  
Yoon Kim ◽  
Gorka Lasso ◽  
Hardik Patel ◽  
Badri Vardarajan ◽  
Ismael Santa-Maria ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Brain ◽  
Receptor Tyrosine Kinase Family

Recently, late onset AD (LOAD) genome-wide association studies identified EphA1, a member of receptor tyrosine kinase family (RTK) as a disease associated loci. In the follow-up study where 3 independent LOAD cohorts were performed, a P460L coding mutation in EphA1 loci showed a significant association with LOAD. However, the role of EphA1 and P460L mutant EphA1 in AD is not fully understood. We have characterized this mutation biophysically and biochemically. Our structural in silico model and in vitro biochemical analysis demonstrate that EphA1-P460L mutation makes the receptor constitutively active suggesting a gain-of-toxic function leading to chronic EphA1 signaling in the brain. Moreover, we report that the EphA1 P460L variant triggers Rho-GTPase signaling dysregulation that could potentially contribute to spine morphology abnormalities and synaptic dysfunction observed in AD pathology.

scholarly journals Subtypes of Barrett’s oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis

Gut ◽  
2018 ◽  
Vol 68 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Ming Yu ◽  
Sean K Maden ◽  
Matthew Stachler ◽  
Andrew M Kaz ◽  
Jessica Ayers ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Massively Parallel Sequencing ◽  
T Test ◽  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Aberrant Methylation ◽  
Barrett's Oesophagus ◽  
Genome Wide

ObjectiveTo identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett’s oesophagus (BE).DesignWe performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.ResultsWe identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student’s t-test) and the highest global mutation load (p<0.05, Fisher’s exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch’s t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.ConclusionsWe identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

scholarly journals Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring

AGE ◽  
2012 ◽  
Vol 35 (5) ◽  
pp. 1961-1973 ◽  
Author(s):  
Davide Gentilini ◽  
Daniela Mari ◽  
Davide Castaldi ◽  
Daniel Remondini ◽  
Giulia Ogliari ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylation Profile ◽  
Human Aging ◽  
Genome Wide ◽  
Dna Methylation Profile

scholarly journals Genome-Wide DNA Methylation Profile in Whole Blood of Patients With Chronic Spontaneous Urticaria

2021 ◽  
Vol 12 ◽  
Author(s):  
Yumeng Qi ◽  
Liming Zhang ◽  
Xiaonan Yang ◽  
Biao Tang ◽  
Ting Xiao
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Methylation Profile ◽  
Thyroid Peroxidase ◽  
Healthy Controls ◽  
Chinese Han ◽  
Han Ethnicity ◽  
Genome Wide ◽  
Dna Methylation Profile

BackgroundChronic spontaneous urticaria (CSU) is a common autoimmune skin disease. Little is known about the role of epigenetics in the pathogenesis of CSU. This study aimed to investigate genome-wide DNA methylation profile in whole blood of patients with CSU.Patients and MethodsGenome-wide DNA methylation levels in whole blood samples of 95 Chinese Han ethnicity adult CSU patients and 95 ethnicity-, age- and sex-matched healthy controls were analyzed using Illumina 850K methylation chip. The differentially methylated genes (DMGs) were screened out and then functionally annotated by the gene ontology and the Kyoto encyclopedia of genes and genomes databases.ResultsA total of 439 differentially methylated positions (DMPs) (p &lt; 0.01 and |Δβ| ≥ 0.06) were identified with 380 hypomethylated and 59 hypermethylated. The average global DNA methylation levels of the 439 DMPs in the CSU patients were significantly lower than those in the healthy controls (p &lt; 0.001). The distribution of the 439 DMPs was wide on chromosome 1 to 22 and chromosome X. Chromosome 6 embodied the largest number of DMPs (n = 51) and their annotated genes were predominantly related to autoimmunity. The 304 annotated DMGs were mainly enriched in autoimmune disease- and immune-related pathways. A total of 41 DMPs annotated to 28 DMGs were identified when p &lt; 0.01 and |Δβ| ≥ 0.1. Of the 28 DMGs, HLA-DPB2, HLA-DRB1, PPP2R5C, and LTF were associated with autoimmunity. CSU cases with elevated total IgE, positive anti-thyroid peroxidase IgG autoantibodies, positive anti-thyroglobulin IgG autoantibodies, angioedema, UASday &gt; 4, or recurrent CSU showed phenotype-specific DMPs as compared with cases with normal total IgE, negative anti-thyroid peroxidase IgG autoantibodies, negative anti-thyroglobulin IgG autoantibodies, no angioedema, UASday ≤ 4, or non-recurrent CSU respectively.ConclusionThis study shows a distinct genome-wide DNA methylation profile in Chinese Han ethnicity adult CSU patients and indicates a role of epigenetics in the pathogenesis of CSU. The predominant enrichment of the CSU-associated DMGs in immunological pathways provides supportive evidence for the immunopathogenesis of CSU. Future research on the CSU-associated DMPs and DMGs will help discover potential therapeutic targets for CSU.

scholarly journals Cellular Models in Schizophrenia Research

2021 ◽  
Vol 22 (16) ◽  
pp. 8518
Author(s):  
Dmitrii A. Abashkin ◽  
Artemii O. Kurishev ◽  
Dmitry S. Karpov ◽  
Vera E. Golimbet
Keyword(s):  
Brain Function ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Cellular Models ◽  
Transcriptional Dysregulation ◽  
Functional Psychosis ◽  
Biological Phenomena ◽  
Genome Wide

Schizophrenia (SZ) is a prevalent functional psychosis characterized by clinical behavioural symptoms and underlying abnormalities in brain function. Genome-wide association studies (GWAS) of schizophrenia have revealed many loci that do not directly identify processes disturbed in the disease. For this reason, the development of cellular models containing SZ-associated variations has become a focus in the post-GWAS research era. The application of revolutionary clustered regularly interspaced palindromic repeats CRISPR/Cas9 gene-editing tools, along with recently developed technologies for cultivating brain organoids in vitro, have opened new perspectives for the construction of these models. In general, cellular models are intended to unravel particular biological phenomena. They can provide the missing link between schizophrenia-related phenotypic features (such as transcriptional dysregulation, oxidative stress and synaptic dysregulation) and data from pathomorphological, electrophysiological and behavioural studies. The objectives of this review are the systematization and classification of cellular models of schizophrenia, based on their complexity and validity for understanding schizophrenia-related phenotypes.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

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