DNA Methylation as a Biomarker for Cardiovascular Disease Risk

Kim, Myung-Jin; Long, Theodore; Arakawa, Kazuko; Wang, Renwei; Yu, Mimi C.; Laird, Peter W.

doi:10.1371/journal.pone.0009692

Cited by 303 publications

(223 citation statements)

References 26 publications

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“…In this regard, epigenetic factors are emerging as an area of great interest on account of being modifiable through extracellular stresses, including air pollution, in contrast to genetic factors. Subsequently, many studies have assessed the effect of air pollution on global genomic DNA methylation (Alu, Satellite 2, and LINE‐1 repetitive elements) and gene‐specific DNA methylation (eg, ALOX15 , AMOTL2 , ARHGAP24 , IGF2 , and PECAM ), mainly using blood cells as a surrogate marker 18, 19, 20, 21, 22. For the first time, we have demonstrated a potential role for mtDNA methylation in the association between PM 2.5 exposure and CVD risk.…”

Section: Discussionmentioning

confidence: 99%

Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability

Byun

Colicino

Trevisi

et al. 2016

JAHA

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BackgroundThe mitochondrion is the primary target of oxidative stress in response to exogenous environments. Mitochondrial DNA (mtDNA) is independent from nuclear DNA and uses separate epigenetic machinery to regulate mtDNA methylation. The mtDNA damage induced by oxidative stress can cause mitochondrial dysfunction and is implicated in human diseases; however, mtDNA methylation has been largely overlooked in environmental studies relating to human disease. The purpose of this study was to examine the association between exposure to fine metal‐rich particulates (particulate matter <2.5 µm in diameter [PM 2.5]) from welding in a boilermaker union and blood mtDNA methylation in relation to heart rate variability.Methods and ResultsForty‐eight healthy men were recruited on multiple sampling cycles at the Boilermaker Union Local 29, located in Quincy, Massachusetts. We measured personal PM 2.5 in the background ambient environment. We measured blood mtDNA methylation in the mtDNA promoter (D‐loop) and genes essential for ATP synthesis (MT‐TF and MT‐RNR1) by bisulfite pyrosequencing. All analyses were adjusted for demographics, type of job, season, welding‐work day, and mtDNA methylation experimental batch effect. The participants’ PM 2.5 exposure was significantly higher after a welding‐work day (mean 0.38 mg/m3) than the background personal level (mean 0.15 mg/m3, P<0.001). Blood mtDNA methylation in the D‐loop promoter was associated with PM 2.5 levels (β=−0.99%, SE=0.41, P=0.02). MT‐TF and MT‐RNR1 methylation was not associated with PM 2.5 exposure (β=0.10%, SE=0.45, P=0.82). Interaction of PM 2.5 exposure levels and D‐loop promoter methylation was significantly associated with markers of heart rate variability.ConclusionsBlood mtDNA methylation levels were negatively associated with PM 2.5 exposure and modified the adverse relationships between PM 2.5 exposure and heart rate variability outcomes.

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Section: Discussionmentioning

confidence: 99%

Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability

Byun

Colicino

Trevisi

et al. 2016

JAHA

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“…18,19 Previous studies have suggested that DNA methylation in these types of sequences may play a role in complex diseases other than cancer, such as cardiovascular diseases and diabetes. 9,10,20 It is well known that DNA methylation is a dynamic process and it is affected by environmental factors, both from development in uterus (intrauterine development) and in adult life. Several of these environmental exposures are associated with the risk of complex diseases.…”

Section: Discussionmentioning

confidence: 99%

“…6 Although most epigenetic studies have been focused on cancer, 7,8 , previous studies have suggested that DNA methylation in these LINE-1 elements may play a role in other complex human diseases, such as cardiovascular disease or diabetes. [9][10][11][12] However, there are still many unresolved issues about the role of epigenetic changes in the study of complex diseases.…”

Section: Introductionmentioning

confidence: 99%

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: A cohort study

et al. 2014

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In the last years, epigenetic processes have emerged as a promising area of complex diseases research. DNA methylation measured in Long Interspersed Nucleotide Element 1 (LINE-1) sequences has been considered a surrogate marker for global genome methylation. New findings have suggested the potential involvement of epigenetic mechanisms in Type 2 diabetes (T2DM) as a crucial interface between the effects of genetic predisposition and environmental influences. Our study evaluated whether global DNA methylation predicted increased risk from T2DM or other carbohydrate metabolism disorders in a cohort study. We used a prospective cohort intervention study and a control group. We collected phenotypic, anthropometric, biochemical, and nutritional information from all subjects. Global LINE-1 DNA methylation was quantified by pyrosequencing technology. Subjects that did not improve their carbohydrate metabolism status showed lower levels of global LINE-1 DNA methylation (63.9 § 1.7 vs. 64.7 § 2.4) and they practiced less intense physical activity (5.8% vs. 21.5%). Logistic regression analyses showed a significant association between LINE-1 DNA methylation and metabolic status after adjustment for sex, age, BMI, and physical activity. Our study showed that lower LINE-1 DNA methylation levels were associated with a higher risk metabolic status worsening, independent of other classic risk factors. This finding highlights the potential role for epigenetic biomarkers as predictors of T2DM risk or other related metabolic disorders.

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“…In humans, a loss of genomic DNA methylation has been described to occur in several types of tissue during aging and age-related diseases (Fraga et al 2007;Bollati et al 2009;Kim et al 2010;Choi et al 2009;Moore et al 2008). In addition, global genomic hypomethylation of leukocyte DNA has been reported to be an independent risk factor for cancer, atherosclerosis, and cardiovascular disease (Fraga et al 2007;Kim et al 2010;Choi et al 2009;Moore et al 2008). DNA hypomethylation occurs mostly in transposable DNA repetitive elements, including the Alu and LINE-1 sequences, which play a crucial role in gene regulation and genomic stability.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of global DNA methylation and promoter hypermethylation of several specific genes occur during aging. Epigenetics plays an important role in cellular senescence, human tumorigenesis, and several agerelated diseases (Fraga et al 2007;Bollati et al 2009;Kim et al 2010;Choi et al 2009;Moore et al 2008;Rakyan et al 2010;Chambers et al 2007). Indeed, epigenomic alterations are now increasingly recognized as part of aging and its associated pathologic phenotype (Petronis 2010;Bellizzi et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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

Gentilini

Mari

Castaldi

et al. 2012

AGE

180

120

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The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG AGE (2013) 35:1961-1973 DOI 10.1007 islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genomewide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulinlike growth factor I system impairment on the modulation of human lifespan.

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DNA Methylation as a Biomarker for Cardiovascular Disease Risk

Cited by 303 publications

References 26 publications

Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability

Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: A cohort study

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

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