Search

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Women’s Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p

Type 2 diabetes (T2D) in youth is diagnosed after irreparable islet damage. Cell-free DNA methylation can be used as a marker of islet cell death after islet transplantation. We assessed the performance of cell-free (cf) DNA in the discrimination of T2D and as a circulating biomarker of islet cell death. Methods: We recruited 72 youth 10-20 years old through provider networks in Atlanta, Georgia. Participant groups were (a) new onset T2D (n=21, within 16 weeks of diagnosis) ; (b) healthy, normal weight (n=23, no family history of diabetes) ; and (c) High Risk (HR, n=31, BMI ≥ 95th %ile or acanthosis nigricans; with family history) . All participants had an oral glucose tolerance test. Based on genes uniquely unmethylated in islets, plasma was analyzed at 9 CpG sites across 3 genes (INS, GCK, IADD) using bisulfite conversion and next generation sequencing. T2D and HR were grouped and compared to Healthy by (a) linear regression of % methylation on group, and (b) area under the curve (AUC) ROC analysis, adjusted for age and BMI %ile. Results: Mean age was higher among healthy participants (17yr SD±3) vs. T2D+HR (14±2) . Age- & BMI %ile- adjusted methylation of INS GRCh38 CpG Chr11:2160843 was highest in T2D+HR (94.8%, 95%CI: 93.5, 96.1) and lowest in Healthy (90.0%, 95%CI: 87.7, 92.2) , p=0.0051. Secondly, at CpG Chr11:2160806, methylation was highest in T2D+HR (85.6%, 95%CI: 83.3, 87.8) vs. Healthy (83.1%, 95%CI: 79.1, 87.1) , p=0.0409. Cell-free INS methylation improved the AUC for T2D or severe prediabetes (i.e., combined impaired fasting glucose + impaired glucose tolerance, per ADA cutpoints) from 0.72 in models of age and BMI %ile to 0.81 in models also including cfINS methylation. Conclusions: Higher % methylated cfINS was found in T2D+HR youth, rather than hypothesized lower levels. It is possible that during T2D onset, non-islet apoptosis occurs in larger concentration than islet cell apoptosis. Methylated cfINS improved discrimination of T2D and severe prediabetes by nearly 10% beyond age and BMI. Disclosure L.R.Staimez: None. J.Ham: None. T.Daley: None. P.Vellanki: n/a. A.K.Smith: None. K.Narayan: n/a. A.Baccarelli: None. K.Conneely: None. Funding Georgia CTSA UL1 (UL1TR002378) and KL2 (KL2TR002381) ; Emory University Woodruff Health Sciences Center Foundation

Bisulfite sequencing (BS-seq) technology has enabled the detection and measurement of DNA methylation at the single-nucleotide level. A fundamental question in functional epigenomics research is whether DNA methylation varies under different biological contexts. Thus, identifying differentially methylated loci/regions (DML/DMRs) is a key task in BS-seq data analysis. Here we describe detailed procedures to perform differential methylation analyses for BS-seq using the Bioconductor package DSS. The analysis scheme in this chapter will guide researchers through differential methylation analyses by providing step-by-step instructions for analytical tools.

Background Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.

Social exposures may drive epigenetic alterations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer.Genome-wide DNA methylation was measured using the EPIC array in the tumor tissue of 96 women. Linear regression models were used to examine the association between nine neighborhood-level factors and methylation, regressing β values for each cytosine-phosphate guanine dinucleotide (CpG) site on neighborhood-level factors while adjusting for covariates. Neighborhood data were obtained from the Opportunity Atlas. We used a false discovery rate (FDR) threshold 0.05, and for CpGs below this threshold, we examined interactions with race. We employed multivariable Cox proportional-hazards models to estimate whether aberrant methylation was associated with all-cause mortality.26 of the CpG sites were associated with job density or college education (FDR 0.05). Further exploration of these 26 CpG sites revealed no interactions by race, but a single probe in TMEM204 was associated with all-cause mortality.We identified novel associations between neighborhood-level factors and the breast tumor DNA methylome. Our data are the first to show that dysregulation in neighborhood associated CpG sites may be associated with all-cause mortality. Neighborhood-level factors may contribute to differential tumor methylation in genes related to tumor progression and metastasis. This contributes to the increasing body of evidence that area-level factors (such as neighborhood characteristics) may play an important role in cancer disparities through modulation of the breast tumor epigenome.

As a primary risk factor and modifier of breast cancer incidence and prognosis, obesity may contribute to race disparities in breast cancer outcomes. This study examined association between obesity and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer.Genome-wide DNA methylation was measured in the breast cancer tumor tissue of 96 women using the EPIC array. To examine the association between obesity and tumor methylation, linear regression models were used-regressing methylation β value for each cytosine and guanine (CpG) site on body mass index adjusting for covariates. Significance was set at false discovery rate (FDR) 0.05. In the top 20 CpG sites, we explored the interactions with race and estrogen receptor (ER) status. We used multivariable Cox-proportional hazard models to examine whether methylation in the top 20 sites was associated with all-cause mortality.While none of the CpG sites passed the FDR threshold for significance, among the top 20 CpG sites, we observed interactions with race (TOMM20) and ER status (PSMB1, QSOX1 and PHF1). The same CpG sites in TOMM20, PSMB1, and QSOX1 were associated with all-cause mortality.We identified novel interactions between obesity-associated methylation and both race and ER status in genes that have been associated with tumor regulation. Our data suggest that dysregulation in two sites may associate with all-cause mortality.

Background Although inflammatory bowel disease (IBD) is heritable, the heritability is still largely unexplained despite substantial progress through GWAS and WGS. However, recent advances in epigenetics (gene environmental interactions), including DNA methylation (DNAm) analysis, has identified new disease-specific mechanisms controlling gene expression. We recently showed that IBD-associated blood DNAm patterns strongly correlated with inflammation (CRP as surrogate marker) and reverted to patterns seen in healthy controls following treatment, regardless of whether or not the underlying IBD was in remission, suggesting blood DNAm is more representative of the systemic inflammatory status rather than disease status (Gastroenterology, 2019, 156 (8): 2254–2265). Thus, we aimed to study DNAm patterns in rectal biopsies hypothesizing that DNAm in rectal biopsies will reflect disease status rather than systemic inflammatory status alone. Method Genome-wide DNA methylation was measured using the Illumina MethylationEPIC array on rectal biopsy DNA samples of 85 non-inflammatory, non-IBD controls and 215 newly diagnosed ulcerative colitis (UC) patients prior to therapy, along with 49 one-year follow-up UC cases (PROTECT cohort) to identify disease specific methylation patterns. Epigenome wide association studies (EWAS) were performed with UC and CRP as the outcomes in linear models adjusted for age, gender, race and five genotype-based principal components. Results At diagnosis, 2446 disease-specific CpG sites in rectal tissue (FDR Conclusion When studied longitudinally, the UC-specific DNA methylation patterns in rectal tissue are distinct from blood samples. In contrast to blood DNAm which normalizes after therapy during follow-up, rectal tissue DNAm changes persist after treatment in UC. This suggests the currently available therapies control the systemic inflammation effectively, but have less direct effect on the disease itself. Future therapies targeting disease-specific DNAm may be more effective in disease management and long-term remission.

PurposeThe purpose of this paper is to show the benefits to be obtained from radio frequency ID (RFID) for improved asset management and accountability.Design/methodology/approachExamines the technology's potential for asset management across industry sectors.FindingsFinds that the majority of companies have very little grasp of how inaccurate the asset register can be, believing stored data could only be a maximum of 5 per cent inaccurate. RFID tags allow those responsible for managing fixed assets far greater visibility into the true condition and value of those assets. For example, workers of heavy machinery, such as mechanics and drivers, can gain instant insight to all the machinery parts' maintenance history as well as information on unique identifiers including part numbers, serial numbers and manufacturers' codes.Practical implicationsBy adopting RFID, scanning can be undertaken by line managers on a regular basis in a matter of minutes, without impacting the organisation's core operations in any way. The tight integration with the full asset history and general ledger ensures unprecedented accuracy and auditability of the entire asset register.Originality/valueDraws attention to the benefits of RFID and the current under‐utilisation of this established technology.

In their controversial book The Bell Curve, Richard Herrnstein and Charles Murray summarize an impressive body of research on the correlations between social outcomes and scores on tests of cognitive ability.1 A remarkable finding of the research they survey is that one linear combination of tests—called general intelligence, or g—predicts performance almost as well as the full battery of tests.