Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study

Li, Chengchen; Wang, Zeyuan; Hardy, Theresa M.; Huang, Yunfeng; Hui, Qin; Crusto, Cindy A.; Wright, Michelle L.; Taylor, Jacquelyn Y.; Sun, Yan V.

doi:10.3390/ijms20174273

Cited by 29 publications

(37 citation statements)

References 34 publications

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“…Our observations suggest that higher pre-pregnancy BMI may lead to higher biological burden relative to cellular aging. This finding is supported by existing literature in both pregnant and non-pregnant individuals, 28,33,34 and may provide insight into age-related disease outcomes. Because it is as a modifiable factor, BMI represents an important clinical target to improve outcomes.…”

Section: Discussionsupporting

confidence: 86%

Racial Differences in DNA Methylation-Based Age Acceleration in Preeclamptic and Normotensive Pregnancy

Heinsberg

Ray

Conley

et al. 2020

Preprint

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Background: Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with increased risk of preeclampsia; however, the pathophysiology of preeclampsia and how these risk factors impact its development, are not entirely understood. This gap precludes clinical interventions to prevent preeclampsia occurrence or to address stark racial disparities in maternal and neonatal outcomes. Of note, cellular aging rates can differ between individuals and chronological age is often a poor surrogate of biological age. DNA methylation age provides a marker of biological aging, and those with a DNA methylation age greater than their chronological age have "age acceleration". Examining age acceleration in the context of preeclampsia status, and race, could strengthen our understanding of preeclampsia pathophysiology, inform future interventions to improve maternal/neonatal outcomes, and provide insight to racial disparities across pregnancy. Objectives: The purpose of this exploratory study was to examine associations between age acceleration, preeclampsia status, and race across pregnancy. Study design: This was a longitudinal, observational, case-control study of 56 pregnant individuals who developed preeclampsia (n=28) or were normotensive controls (n=28). Peripheral blood samples were collected at trimester-specific time points and genome-wide DNA methylation data were generated using the Infinium MethylationEPIC Beadchip. DNA methylation age was estimated using the Elastic Net "Improved Precision" clock and age acceleration was computed as Δage, the difference between DNA methylation age and chronological age. DNA methylation age was compared with chronological age using scatterplots and Pearson correlations, while considering preeclampsia status and race. The relationships between preeclampsia status, race, and Δage were formally tested using multiple linear regression, while adjusting for pre-pregnancy body mass index, chronological age, and (chronological age)2. Regressions were performed both with and without consideration of cell-type heterogeneity. Results: We observed strong correlations between chronological age and DNA methylation age in all trimesters, ranging from R=0.91-0.95 in cases and R=0.86-0.90 in controls. We observed significantly stronger correlations between chronological age and DNA methylation age in White versus Black participants ranging from R=0.89-0.98 in White participants and R=0.77-0.83 in Black participants. We observed no association between Δage and preeclampsia status within trimesters. However, even while controlling for covariates, Δage was higher in trimester 1 in participants with higher pre-pregnancy BMI (β=0.12, 95% CI=0.02 to 0.22, p=0.02) and lower in Black participants relative to White participants in trimesters 2 (β=-2.68, 95% CI=-4.43 to -0.94, p=0.003) and 3 (β=-2.10, 95% CI=-4.03 to -0.17, p=0.03). When controlling for cell-type heterogeneity, the observations with BMI in trimester 1 and race in trimester 2 persisted. Conclusions: We report no association between Δage and preeclampsia status, although there were associations with pre-pregnancy BMI and race. In particular, our findings in a small sample demonstrate the need for additional studies to not only investigate the complex pathophysiology of preeclampsia, but also the relationship between race and biological aging, which could provide further insight into racial disparities in pregnancy and birth. Future efforts to confirm these findings in larger samples, including exploration and applications of other epigenetic clocks, is needed.

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Section: Discussionsupporting

confidence: 86%

Racial Differences in DNA Methylation-Based Age Acceleration in Preeclamptic and Normotensive Pregnancy

Heinsberg

Ray

Conley

et al. 2020

Preprint

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“…Nevalainen et al [42] found increased epigenetic age estimates in middle-aged individuals with high BMI. These findings were supported by data of Simpkin et al [43], McCartney et al [32], Li et al [44] and Thurston et al [29]. Recently, Fiorito et al [27] published data from a large multicohort study (n = 16,245), revealing increased epigenetic age estimates of up to 1.08 years (p < 0.001) for individuals with high BMI (BMI ≥ 30).…”

Section: Obesity Fosters Epigenetic Ageingmentioning

confidence: 52%

Epigenetic clocks may come out of rhythm—implications for the estimation of chronological age in forensic casework

et al. 2020

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There is a growing perception that DNA methylation may be influenced by exogenous and endogenous parameters. Knowledge of these factors is of great relevance for the interpretation of DNA-methylation data for the estimation of chronological age in forensic casework. We performed a literature review to identify parameters, which might be of relevance for the prediction of chronological age based on DNA methylation. The quality of age predictions might particularly be influenced by lifetime adversities (chronic stress, trauma/post-traumatic stress disorder (PTSD), violence, low socioeconomic status/education), cancer, obesity and related diseases, infectious diseases (especially HIV and Cytomegalovirus (CMV) infections), sex, ethnicity and exposure to toxins (alcohol, smoking, air pollution, pesticides). Such factors may alter the DNA methylation pattern and may explain the partly high deviations between epigenetic age and chronological age in single cases (despite of low mean absolute deviations) that can also be observed with “epigenetic clocks” comprising a high number of CpG sites. So far, only few publications dealing with forensic age estimation address these confounding factors. Future research should focus on the identification of further relevant confounding factors and the development of models that are “robust” against the influence of such biological factors by systematic investigations under targeted inclusion of diverse and defined cohorts.

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“…For many African Americans (AA), experiencing violence, discrimination, and environmentally induced stressors, such as childhood neglect or abuse, are well documented ( Jacobs et al., 2014 ; Pew Research Center, 2016 ). AAs carry a disproportionate burden of incidence, morbidity, and mortality from chronic diseases such as hypertension and obesity ( Allport et al., 2019 ; Barengolts et al., 2019 ; Yang et al., 2019 ; Li et al., 2019 ; Faucher et al., 2019 ; Assari et al., 2019 ; Nagy et al., 2020 ; Goode et al., 2017 ; Go et al., 2014 ) in addition to exposure to violence (ETV) which has also been shown to have a negative impact on health ( Griggs et al., 2019 ; Goldmann et al., 2011 ; Woodson et al., 2010 ; Paranjape and Kaslow, 2010 ; Mitchell et al., 2010 ; Paranjape et al., 2009 ; McGee et al., 2001 ; Moffitt and Klaus-Grawe Think, 2013 ; Olofsson et al., 2012 ). Therefore, it is worthwhile to examine if lifetime exposure to violence is a contributing factor in AA health disparity.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and exposure to violence among African American young adult males

Saadatmand

Gurdziel

Jackson

et al. 2021

Brain, Behavior, & Immunity - Health

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Exposure to violence (ETV) has been linked to epigenomics mechanisms such as DNA methylation (DNAm). We used epigenetic profiling of blood collected from 32 African American young adult males who lived in Washington DC to determine if changes in DNAm at CpG sites affiliated with nervous and immune system were associated with exposure to violence. Pathway analysis of differentially methylated regions comparing high and low ETV groups revealed an enrichment of gene sets annotated to nervous system and immune ontologies. Many of these genes are known to interact with each other which suggests DNAm alters gene function in the nervous and immune system in response to ETV. Using data from a unique age group, young African American adult males, we provide evidence that lifetime ETV could impact DNA methylation in genes impacted at Central Nervous System and Immune Function sites. Method Methylation analysis was performed on DNA collected from the blood of participants classified with either high or low lifetime ETV. Illumina®MethylationEPIC Beadchips (~850k CpG sites) were processed on the iScan System to examine whole-genome methylation differences. Differentially methylated CpG-sites between high (n = 19) and low (n = 13) groups were identified using linear regression with violence and substance abuse as model covariates. Gene ontology analysis was used to identify enrichment categories from probes annotated to the nearest gene. Results A total of 595 probes (279 hypermethylated; 316 hypomethylated) annotated to 383 genes were considered differentially methylated in association with ETV. Males with high ETV showed elevated methylation in several signaling pathways but were most impacted at Central Nervous System and Immune Function affiliated sites. Eight candidate genes were identified that play important biological roles in stress response to violence with HDAC4 (10%), NR4A3 (11%), NR4A2 (12%), DSCAML1(12%), and ELAVL3 (13%) exhibiting higher levels in the low ETV group and DLGAP1 (10%), SHANK2 (10%), and NRG1(11%) having increased methylation in the high ETV group. These findings suggest that individuals subjected to high ETV may be at risk for poor health outcomes that have not been reported previously.

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Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study

Cited by 29 publications

References 34 publications

Racial Differences in DNA Methylation-Based Age Acceleration in Preeclamptic and Normotensive Pregnancy

Racial Differences in DNA Methylation-Based Age Acceleration in Preeclamptic and Normotensive Pregnancy

Epigenetic clocks may come out of rhythm—implications for the estimation of chronological age in forensic casework

DNA methylation and exposure to violence among African American young adult males

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