Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases

Chilunga, Felix P; Henneman, Peter; Venema, Andrea; Meeks, Karlijn; Requena‐Méndez, Ana; Beune, Erik; Mockenhaupt, Frank P.; Smeeth, Liam; Bahendeka, Silver; Klipstein‐Grobusch, Kerstin; Adeyemo, Adebowale; Mannens, Marcel M.A.M.; Agyemang, Charles

doi:10.1038/s41525-021-00213-9

Cited by 7 publications

(4 citation statements)

References 68 publications

(99 reference statements)

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“…Second, in the present study, we have demonstrated that, above a cut-off of 20 mg/L, CRP levels become inversely associated with epigenetic age acceleration. This might be a “paradoxical” statistical artifact (due to the six out of 72 subjects falling in this group), but, in our opinion, because of the association of epigenetic loci in its gene with inflammation and CVD [ 37 ], CRP might become the “perpetrator and victim” of the same obesity-related DNA destabilization previously described [ 38 , 39 , 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 94%

Effect of a 3-Week Multidisciplinary Body Weight Reduction Program on the Epigenetic Age Acceleration in Obese Adults

Rigamonti

Bollati

Favero

et al. 2022

JCM

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Obesity and aging share common molecular and cellular mechanisms underlying the pathophysiology of cardiovascular diseases (CVD), which occur frequently in both conditions. DNA methylation (DNAm) age, a biomarker of the epigenetic clock, has been proposed as a more accurate predictor of biological aging than chronological age. A positive difference between an individual’s chronological age and DNAm age is referred to as epigenetic age acceleration. The objective of the present study was to evaluate the effects of a 3-week in-hospital body weight reduction program (BWRP) on the epigenetic age acceleration, as well as on other cardiometabolic outcomes, in a cohort of 72 obese adults (F/M: 43/29; (chronological) age: 51.5 ± 14.5 yrs; BMI: 46.5 ± 6.3 kg/m2). At the end of the BWRP, when considering the entire population, BMI decreased, and changes in body composition were observed. The BWRP also produced beneficial metabolic effects as demonstrated by decreases in glucose, insulin, HOMA-IR, total cholesterol, and LDL cholesterol. A post-BWRP improvement in cardiovascular function was also evident (i.e., decreases in systolic and diastolic blood pressures and heart rate). The BWRP reduced some markers of systemic inflammation, particularly C-reactive protein (CRP). Finally, vascular age (VA) and Framingham risk score (FRS) were reduced after the BWRP. When considering the entire population, DNAm age and epigenetic age acceleration did not differ after the BWRP. However, when subdividing the population into two groups based on each subject’s epigenetic age acceleration (i.e., ≤0 yrs or >0 yrs), the BWRP reduced the epigenetic age acceleration only in obese subjects with a value > 0 yrs (thus biologically older than expected). Among all the single demographic, lifestyle, biochemical, and clinical characteristics investigated, only some markers of systemic inflammation, such as CRP, were associated with the epigenetic age acceleration. Moreover, chronological age was correlated with DNAm age and VA; finally, there was a correlation between DNAm age and VA. In conclusion, a 3-week BWRP is capable of reducing the epigenetic age acceleration in obese adults, being the BWRP-induced rejuvenation evident in subjects with an epigenetic age acceleration > 0 yrs. Based on the BWRP-induced decrease in CRP levels, chronic systemic inflammation seems to play a role in mediating obesity-related epigenetic remodeling and biological aging. Thus, due to the strong association of CVD risk with the epigenetic clock and morbidity/mortality, any effort should be made to reduce the low-grade chronic inflammatory state in obesity.

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Section: Discussionmentioning

confidence: 94%

Effect of a 3-Week Multidisciplinary Body Weight Reduction Program on the Epigenetic Age Acceleration in Obese Adults

Rigamonti

Bollati

Favero

et al. 2022

JCM

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“…A look-up analysis using the EWAS Catalog revealed that 1,496 associations (4.4%) from the basic model were previously reported in the literature 6,7,26,35,36 . Effect sizes for 1,379 significant CpG associations in the largest existing EWAS on CRP were correlated 97% with corresponding associations in our study 6 (Additional file 4: Fig.…”

Section: Epigenome-wide Association Study To Identify Individual Cpg ...mentioning

confidence: 85%

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts

Hillary,

Ng,

McCartney

et al. 2023

Preprint

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Chronic inflammation is a hallmark of ageing and age-related disease states. The effectiveness of inflammatory proteins such as C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N=17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic net regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the LBC1936 cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (ALSPAC, HELIOS, SABRE, LBC1921), including individuals of diverse genetic ancestry and from different age groups. The newly-described predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

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“…Methylation is most commonly observed at so-called CpG islands [ 3 ], which are long repeats of cytosine-guanine nucleotides. As technologies to study genome-wide DNA methylation continue to develop, there is growing evidence that there is a strong link between DNA methylation and CVD [ 4 – 6 ]. However, there is still little to no evidence of the directionality of this relationship, and clear findings on relevant CpG sites or genes have not yet emerged from the extensive research in this area.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites

et al. 2023

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Background Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking. Results A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function “DNA-binding transcription activator activity” (q = 1.65 × 10–11) and biological processes “skeletal system development” (q = 1.89 × 10–23). Gene enrichment demonstrated that general CVD-related terms are shared, while “heart” and “vasculature” specific genes have more disease-specific terms as PR interval for “heart” or platelet distribution width for “vasculature.” STRING analysis revealed significant protein–protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10–6) and atherosclerosis (p = 4.9 × 10–4). Conclusion This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.

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Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases

Cited by 7 publications

References 68 publications

Effect of a 3-Week Multidisciplinary Body Weight Reduction Program on the Epigenetic Age Acceleration in Obese Adults

Effect of a 3-Week Multidisciplinary Body Weight Reduction Program on the Epigenetic Age Acceleration in Obese Adults

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts

DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites

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