Thousands of CpGs Show DNA Methylation Differences in ACPA-Positive Individuals.
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ABSTRACT:
SUBMITTER: Zeng Y
PROVIDER: S-EPMC8472734 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. METHODS:With banked serum from a random subset (N?=?3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to "validate" the differentially methylated sites. RESULTS:We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. CONCLUSIONS:Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.
| S-EPMC6668183 | biostudies-literature
Project description:BACKGROUND:In recent years, epigenetics has gained a central role in the understanding of the process of natural selection. It is now clear how environmental impacts on the methylome could promote methylation variability with direct effects on disease etiology as well as phenotypic and genotypic variations in evolutionary processes. To identify possible factors influencing inter-individual methylation variability, we studied methylation values standard deviation of 166 healthy individuals searching for possible associations with genomic features and evolutionary signatures. RESULTS:We analyzed methylation variability values in relation to CpG cluster density and we found a strong association between them (p-value <?2.2?×?10-?16). Furthermore, we found that genes related to CpGs with high methylation variability values were enriched for immunological pathways; instead, those associated with low ones were enriched for pathways related to basic cellular functions. Finally, we found an association between methylation variability values and signals of both ancient (p-value <?2.2?×?10-?16) and recent selective pressure (p-value <?1?×?10-?4). CONCLUSION:Our results indicate the presence of an intricate interplay between genetics, epigenetic code and evolutionary constraints in humans.
| S-EPMC5880022 | biostudies-literature
Project description:Allele-specific expression is when one allele of a gene shows higher levels of expression compared with the other allele, in a diploid organism. Recent work has identified allele-specific expression in a number of Hymenopteran species. However, the molecular mechanism which drives this allelic expression bias remains unknown. In mammals, DNA methylation is often associated with genes which show allele-specific expression. DNA methylation systems have been described in species of Hymenoptera, providing a candidate mechanism. Using previously generated RNA-Seq and whole-genome bisulfite sequencing from reproductive and sterile bumblebee (Bombus terrestris) workers, we have identified genome-wide allele-specific expression and allele-specific DNA methylation. The majority of genes displaying allele-specific expression are common between reproductive and sterile workers and the proportion of allele-specific expression bias generally varies between genetically distinct colonies. We have also identified genome-wide allele-specific DNA methylation patterns in both reproductive and sterile workers, with reproductive workers showing significantly more genes with allele-specific methylation. Finally, there is no significant overlap between genes showing allele-specific expression and allele-specific methylation. These results indicate that cis-acting DNA methylation does not directly drive genome-wide allele-specific expression in this species.
| S-EPMC7502211 | biostudies-literature
Project description:BACKGROUND:Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS:To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N?=?533) and Framingham Heart Study (FHS) (N?=?1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS:Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P?<?5?×?10-?8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P?<?5?×?10-?8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P?=?5.24?×?10-?12), as well as the TFAM knockout methylation (P?= 4.41?×?10-?4) and expression (P?= 4.30?×?10-?4) studies. CONCLUSIONS:These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
| S-EPMC7523322 | biostudies-literature
Project description:ObjectivesAnticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression.Methods103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12?months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed.ResultsCompared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4?months, respectively).ConclusionsT cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression.
| S-EPMC5036223 | biostudies-literature
Project description:In humans the expression of lactase changes during post-natal development, leading to phenotypes known as lactase persistence and non-persistence. Polymorphisms within the lactase gene (LCT) enhancer, in particular the -13910C?>?T, but also others, are linked to these phenotypes. We were interested in identifying dynamic mediators of LCT regulation, beyond the genotype at -13910C?>?T. To this end, we investigated two levels of lactase regulation in human intestinal samples obtained from New England children and adolescents of mixed European ancestry: differential expression of transcriptional regulators of LCT, and variations in DNA methylation, and their relation to phenotype. Variations in expression of CDX2, POU2F1, GATA4, GATA6, and HNF1? did not correlate with phenotype. However, an epigenome-wide approach using the Illumina Infinium HM450 bead chip identified a differentially methylated position in the LCT promoter where methylation levels are associated with the genotype at -13910C?>?T, the persistence/non-persistence phenotype and lactase enzymatic activity. DNA methylation levels at this promoter site and CpGs in the LCT enhancer are associated with genotype. Indeed, taken together they have a higher power to predict lactase phenotypes than the genotype alone.
| S-EPMC5884863 | biostudies-literature
Project description:BACKGROUND: Rheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies (GWAS) have only been published from ACPA-positive subsets of RA or from studies that have not separated the two subsets. The aim of the current study is to provide and compare GWAS data for both subsets. METHODS AND RESULTS: GWAS using the Illumina 300K chip was performed for 774 ACPA-negative patients with RA, 1147 ACPA-positive patients with RA and 1079 controls from the Swedish population-based case-control study EIRA. Imputation was performed which allowed comparisons using 1,723,056 single nucleotide polymorphisms (SNPs). No SNP achieved genome-wide significance (2.9 × 10??) in the comparison between ACPA-negative RA and controls. A case-case association study was then performed between ACPA-negative and ACPA-positive RA groups. The major difference in this analysis was in the HLA region where 768 HLA SNPs passed the threshold for genome-wide significance whereas additional contrasting SNPs did not reach genome-wide significance. However, one SNP close to the RPS12P4 locus in chromosome 2 reached a p value of 2 × 10? and this locus can thus be considered as a tentative candidate locus for ACPA-negative RA. CONCLUSIONS: ACPA-positive and ACPA-negative RA display significant risk allele frequency differences which are mainly confined to the HLA region. The data provide further support for distinct genetic aetiologies of RA subsets and emphasise the need to consider them separately in genetic as well as functional studies of this disease.
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Project description:Cord blood is a commonly used tissue in environmental, genetic, and epigenetic population studies due to its ready availability and potential to inform on a sensitive period of human development. However, the introduction of maternal blood during labor or cross-contamination during sample collection may complicate downstream analyses. After discovering maternal contamination of cord blood in a cohort study of 150 neonates using Illumina 450K DNA methylation (DNAm) data, we used a combination of linear regression and random forest machine learning to create a DNAm-based screening method. We identified a panel of DNAm sites that could discriminate between contaminated and non-contaminated samples, then designed pyrosequencing assays to pre-screen DNA prior to being assayed on an array.Maternal contamination of cord blood was initially identified by unusual X chromosome DNA methylation patterns in 17 males. We utilized our DNAm panel to detect contaminated male samples and a proportional amount of female samples in the same cohort. We validated our DNAm screening method on an additional 189 sample cohort using both pyrosequencing and DNAm arrays, as well as 9 publically available cord blood 450K data sets. The rate of contamination varied from 0 to 10% within these studies, likely related to collection specific methods.Maternal blood can contaminate cord blood during sample collection at appreciable levels across multiple studies. We have identified a panel of markers that can be used to identify this contamination, either post hoc after DNAm arrays have been completed, or in advance using a targeted technique like pyrosequencing.
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Project description:Substance-abusing individuals tend to display abnormal reward processing and a vulnerability to being impulsive. Detoxified alcoholics show differences in regional brain activation during a monetary incentive delay task. However, there is limited information on whether this uncharacteristic behavior represents a biological predisposition toward alcohol abuse, a consequence of chronic alcohol use, or both.We investigated proposed neural correlates of substance disorder risk by examining reward system activity during a monetary incentive delay task with separate reward prospect, reward anticipation, and reward outcome phases in 30 individuals with and 19 without family histories of alcoholism. All subjects were healthy, lacked DSM-IV past or current alcohol or substance abuse histories, and were free of illegal substances as verified by a urine toxicology screening at the time of scanning. Additionally, we explored specific correlations between task-related nucleus accumbens (NAcc) activation and distinct factor analysis-derived domains of behavioral impulsivity.During reward anticipation, functional magnetic resonance imaging data confirmed blunted NAcc activation in family history positive subjects. In addition, we found atypical activation in additional reward-associated brain regions during additional task phases. We further found a significant negative correlation between NAcc activation during reward anticipation and an impulsivity construct.Overall, results demonstrate that sensitivity of the reward circuit, including NAcc, is functionally different in alcoholism family history positive individuals in multiple regards.
| S-EPMC3677031 | biostudies-literature
Project description:Pleomorphic adenomas (PAs) are the most frequently diagnosed benign salivary gland tumors. Although the majority of PAs are characterized by slow growth, some develop very fast and are more prone to recur. The reason for such differences remains unidentified. In this study, we performed global DNA methylation profiling using the Infinium Human Methylation EPIC 850k BeadChip Array (Illumina) to search for epigenetic biomarkers that could distinguish both groups of tumors. The analysis was performed in four fast-growing tumors (FGTs) and four slow-growing tumors (SGTs). In all, 85 CpG dinucleotides differentiating both groups were identified. Six CpG tags (cg06748470, cg18413218, cg10121788, cg08249296, cg18455472, and cg19930657) were selected for bisulfite pyrosequencing in the extended group of samples. We confirmed differences in DNA methylation between both groups of samples. To evaluate the potential diagnostic accuracy of the selected markers, ROC curves were constructed. We indicated that CpGs included in two assays showed an area under the curve with an acceptable prognostic value (AUC > 0.7). However, logistic regression analysis allowed us to indicate a more optimal model consisting of five CpGs ((1) cg06748470, (2) cg00600454, (3) CpG located in chr14: 77,371,501-77,371,502 (not annotated in GRCh37/hg19), (4) CpG2 located in chr16: 77,469,589-77,469,590 (not annotated GRCh37/hg19), and (5) cg19930657) with AUC > 0.8. This set of epigenetic biomarkers may be considered as differentiating factors between FGT and SGT during salivary gland tumor diagnosis. However, this data should be confirmed in a larger cohort of samples.
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