TY  - JOUR
AB  - BACKGROUND: To date, various epigenetic clocks have been constructed to estimate biological age, most commonly using DNA methylation (DNAm). These include "first-generation" clocks such as DNAmAgeHorvath and "second-generation" clocks such as DNAmPhenoAge and DNAmGrimAge. The divergence of one's predicted DNAm age from chronological age, termed DNAmAge acceleration (AA), has been linked to mortality and various aging-related conditions, albeit with varying findings. In metabolic syndrome (MetS) and type 2 diabetes (T2D), it remains inconclusive which DNAm-based predictor(s) is/are closely related to these two metabolic conditions. Therefore, we examined the cross-sectional associations between seven DNAm-based predictors and prevalent metabolic conditions in participants with methylation data from the KORA study. We also analyzed the longitudinal association with time-to-incident T2D and the relative prognostic value compared to clinical predictors from the Framingham 8-year T2D risk function in predicting incident disease over eight years. RESULTS: GrimAA and PhenoAA difference demonstrated consistently significant associations in the cross-sectional and longitudinal analyses. GrimAA difference reported a larger effect: with prevalent MetS at F4 (odds ratio = 1.09, 95% confidence interval = [1.06-1.13], p = 2.04E-08), with prevalent T2D at F4 (odds ratio = 1.09 [1.04-1.13], p = 1.38E-04) and with time-to-incident T2D (hazards ratio = 1.05 [1.01-1.10], p = 0.02) for each year increase in GrimAA difference. Mortality risk score was significantly associated with both prevalent metabolic conditions but not in the longitudinal analysis. The inclusion of DNAm-based predictor in the model with Framingham clinical predictors improved discriminative ability, albeit not significantly. Notably, the DNAm-based predictor, when fitted separately, showed a discriminative ability comparable to that of the model with clinical predictors. Overall, no clear pattern of significant associations was identified in the epigenetic measures from the "first-generation" clocks. CONCLUSIONS: GrimAA, PhenoAA difference and mortality risk score, derived from the "second-generation" clocks, demonstrated significant associations with both MetS and T2D. These DNAm-based predictors may be useful biomarkers for risk stratification and disease prognosis in our study sample of European ancestry. Further research is warranted to investigate the generalizability of our findings across different ancestries and to examine the underlying shared biological mechanisms.
AU  - Chew, S.M.
AU  - Teumer, A.*
AU  - Matias-Garcia, P.R.
AU  - Gieger, C.
AU  - Winkelmann, J.
AU  - Suhre, K.*
AU  - Herder, C.*
AU  - Rathmann, W.*
AU  - Peters, A.
AU  - Waldenberger, M.
C1  - 74029
C2  - 57037
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Cross-sectional and longitudinal association of seven DNAm-based predictors with metabolic syndrome and type 2 diabetes.
JO  - Clin. Epigenet.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Epigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease hypothesis. OBJECTIVES: To assess the association of maternal lifestyle with offsprings' birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort. METHODS: A three-step analytic pipeline was applied. In 722 mother-child pairs, overall associations between ten maternal lifestyle factors and the offspring's standardized birth weight were first evaluated by multiple linear regression. Three high-dimensional mediation methods, based on sure independence screening and penalized regression, were then applied on the beta methylation matrix to identify candidate CpG mediators in cord blood driving the significant overall associations. Finally, robust and ordinary least squares (OLS) regression-based classical mediation methods were used with candidate CpG probes to assess single- and multiple (parallel and serial)-mediator models on a low-dimensional space. RESULTS: Gestational weight gain (GWG) (β-adj = 0.03; p = 2 × 10-5) and maternal BMI at the beginning of pregnancy (β-adj = 0.036; p = 1 × 10-4) were significantly associated with the offspring's standardized birth weight. High-dimensional mediation analyses identified pooled sets of four (cg19242268 [TCEA2]; cg08461903 [N/A]; cg14798382 [CHERP/C19orf44] and cg21516291 [SLC35C2]) and five (cg17040807 [CYGB]; cg19242268 [TCEA2]; cg26552621 [CIRBP]; cg04457572 [CDH23] and cg06457011 [PLCG1]) candidate CpG mediators related to GWG and BMI at the beginning of pregnancy, respectively. For both exposures, classical mediation analyses revealed a range of significant single- and multiple (both serial and parallel)-mediator models via both robust and OLS regression based approaches. These indicated the likely presence of individual, causally linked multiple, and causally independent multiple mediatory pathways underlying the two significant overall associations. CONCLUSIONS: Our findings support the hypothesis that neonatal health effects related to maternal lifestyle may be partly mediated by epigenetic alterations. Findings also suggest the possible involvement of multiple DNA methylation sites via various mediatory pathways.
AU  - De Silva, K.
AU  - Lundberg-Ulfsdotter, R.*
AU  - Bodén, S.*
AU  - Vinnars, M.T.*
AU  - Ryden, P.*
AU  - West, C.E.*
AU  - Domellöf, M.*
AU  - Harlid, S.*
C1  - 75922
C2  - 58195
TI  - Epigenetic mediation may explain intergenerational associations between maternal obesogenic lifestyle and children's birth weight: Findings from the NorthPop prospective birth cohort.
JO  - Clin. Epigenet.
VL  - 17
IS  - 1
PY  - 2025
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), and SARS-CoV-2 has been linked to changes in DNA methylation (DNAm) patterns. Studies focused on post-SARS-CoV-2 infection and DNAm have been mainly carried out among severe COVID-19 cases or without distinguishing the severity of cases. However, investigations into mild and asymptomatic cases after SARS-CoV-2 infection are limited. In this study, we analyzed DNAm patterns of mild and asymptomatic cases seven months after SARS-CoV-2 infection in a household setting by conducting epigenome-wide association studies (EWAS). RESULTS: We identified DNAm changes at 42 CpG sites associated with anti-SARS-CoV-2 antibody levels. We additionally report EWAS between COVID-19 cases and controls, with the case status being confirmed by either an antibody test or a PCR test. The EWAS with an antibody test case definition identified 172 CpG sites to be differentially methylated, while the EWAS with a PCR test case definition identified 502 CpG sites. Two common sites, namely cg17126990 (annotated to AFAP1L2) and cg25483596 (annotated to PC), were identified to be hypermethylated across the three EWAS. Both CpG sites have been reported to be involved in molecular pathways after SARS-CoV-2 infection. While AFAP1L2 has been found to be upregulated after SARS-CoV-2 infection, the pyruvate carboxylase (PC) activity seems to be affected by SARS-CoV-2 infection resulting in changes to the host cell metabolism. Additionally, an EWAS to assess persistent health restrictions among PCR-confirmed cases showed 40 CpG sites to be differentially methylated. CONCLUSIONS: We detected associations between DNAm in individuals who had asymptomatic and mild SARS-CoV-2 infections as compared to their household controls. These findings contribute to our understanding of the molecular consequences of SARS-CoV-2 infection observed months after infection.
AU  - Hong, P.
AU  - Waldenberger, M.
AU  - Pritsch, M.*
AU  - Gilberg, L.*
AU  - Brand, I.*
AU  - Bruger, J.*
AU  - Frese, J.*
AU  - Castelletti, N.*
AU  - Garí, M.
AU  - Geldmacher, C.*
AU  - Hoelscher, M.*
AU  - Peters, A.
AU  - Matias-Garcia, P.R.
C1  - 74153
C2  - 57345
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Differential DNA methylation 7 months after SARS-CoV-2 infection.
JO  - Clin. Epigenet.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Maternal hormonal status can have long-term effects on offspring metabolic health and is likely regulated via epigenetic mechanisms. We elucidated the effects of maternal thyroid hormones on the epigenetic regulation of leptin (Lep) transcription in adipose tissue (AT) and subsequently investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology. RESULTS: Pregnant mice treated with triiodothyronine (T3) produced offspring with reduced body weight, total fat mass, and gonadal white adipose tissue (gWAT) mass at 6 months of age (treatment: N = 8; control: N = 12). Compared with control offspring, exclusively female offspring of T3-treated mothers presented lower Lep mRNA levels and higher Lep UE methylation in gWAT. In murine preadipocytes, targeted demethylation of the Lep UE via a dCas9-SunTag-TET1 system reduced methylation by ~ 20%, but this effect was insufficient to alter Lep expression or lipid accumulation after differentiation. In human omental visceral AT (OVAT) samples from the Leipzig Obesity BioBank (LOBB, N = 52), LEP UE methylation was associated with body fat percentage, and mediation analysis indicated that leptin serum levels partially mediate this association exclusively in females. CONCLUSION: Findings from the animal model suggest that maternal thyroid hormones influence offspring gWAT Lep expression in a sex-specific manner, potentially through changes in Lep UE methylation. However, in vitro experiments indicate that Lep UE methylation alone is not sufficient to regulate Lep expression or adipocyte lipid accumulation. In humans with obesity, LEP UE methylation is associated with body fat percentage, with leptin serum levels potentially acting as a mediator exclusively in females.
AU  - Müller, L.*
AU  - Oelkrug, R.*
AU  - Mittag, J.*
AU  - Hoffmann, A.
AU  - Ghosh, A.*
AU  - Noé, F.*
AU  - Wolfrum, C.*
AU  - Guiu-Jurado, E.
AU  - Klöting, N.
AU  - Dietrich, A.*
AU  - Blüher, M.
AU  - Kovacs, P.*
AU  - Krause, K.*
AU  - Keller, M.
C1  - 73369
C2  - 57018
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Sex-specific role of epigenetic modification of a leptin upstream enhancer in adipose tissue.
JO  - Clin. Epigenet.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Non-coding 886 (nc886, vtRNA2-1) is a polymorphically imprinted gene. The methylation status of this locus has been shown to be associated with periconceptional conditions, and both the methylation status and the levels of nc886 RNAs have been shown to associate with later-life health traits. We have previously shown that nc886 RNA levels are associated not only with the methylation status of the locus, but also with a genetic polymorphism upstream from the locus. In this study, we describe the genetic and epigenetic regulators that predict lifelong nc886 RNA levels, as well as their association with cardiometabolic disease (CMD) risk factors and events. We utilised six population cohorts and one CMD cohort comprising 9058 individuals in total. The association of nc886 RNA levels, as predicted by epigenetic and genetic regulators, with CMD phenotypes was analysed using regression models, with a meta-analysis of the results. The meta-analysis showed that individuals with upregulated nc886 RNA levels have higher diastolic blood pressure (β = 0.07, p = 0.008), lower HDL levels (β =  - 0.07, p = 0.006) and an increased incidence of type 2 diabetes (OR = 1.260, p = 0.013). Moreover, CMD patients with upregulated nc886 RNA levels have an increased incidence of stroke (OR = 1.581, p = 0.006) and death (OR = 1.290, p = 0.046). In conclusion, we show that individuals who are predicted to present elevated nc886 RNA levels have poorer cardiovascular health and are at an elevated risk of complications in secondary prevention. This unique mechanism yields metabolic variation in human populations, constituting a CMD risk factor that cannot be modified through lifestyle choices.
AU  - Rajić, S.*
AU  - Delerue, T.
AU  - Ronkainen, J.*
AU  - Zhang, R.*
AU  - Ciantar, J.*
AU  - Kostiniuk, D.*
AU  - Mishra, P.P.*
AU  - Lyytikäinen, L.P.*
AU  - Mononen, N.*
AU  - Kananen, L.*
AU  - Peters, A.
AU  - Winkelmann, J.
AU  - Kleber, M.E.*
AU  - Lorkowski, S.*
AU  - Kähönen, M.*
AU  - Lehtimäki, T.*
AU  - Raitakari, O.*
AU  - Waldenberger, M.
AU  - Gieger, C.
AU  - März, W.*
AU  - Harville, E.W.*
AU  - Sebert, S.*
AU  - Marttila, S.*
AU  - Raitoharju, E.*
C1  - 74236
C2  - 57406
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Regulation of nc886 (vtRNA2-1) RNAs is associated with cardiometabolic risk factors and diseases.
JO  - Clin. Epigenet.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Epigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. RESULTS: We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN. CONCLUSIONS: Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable.
AU  - Bui, H.*
AU  - Keshawarz, A.*
AU  - Wang, M.*
AU  - Lee, M.*
AU  - Ratliff, S.M.*
AU  - Lin, L.*
AU  - Birditt, K.S.*
AU  - Faul, J.D.*
AU  - Peters, A.
AU  - Gieger, C.
AU  - Delerue, T.
AU  - Kardia, S.L.R.*
AU  - Zhao, W.*
AU  - Guo, X.*
AU  - Yao, J.*
AU  - Rotter, J.I.*
AU  - Li, Y.*
AU  - Liu, X.*
AU  - Liu, D.*
AU  - Tavares, J.F.*
AU  - Pehlivan, G.*
AU  - Breteler, M.M.B.*
AU  - Karabegović, I.*
AU  - Ochoa-Rosales, C.*
AU  - Voortman, T.*
AU  - Ghanbari, M.*
AU  - van Meurs, J.B.J.*
AU  - Nasr, M.K.*
AU  - Dörr, M.*
AU  - Grabe, H.J.*
AU  - London, S.J.*
AU  - Teumer, A.*
AU  - Waldenberger, M.
AU  - Weir, D.R.*
AU  - Smith, J.A.*
AU  - Levy, D.*
AU  - Ma, J.*
AU  - Liu, C.*
C1  - 72185
C2  - 56443
TI  - Association analysis between an epigenetic alcohol risk score and blood pressure.
JO  - Clin. Epigenet.
VL  - 16
IS  - 1
PY  - 2024
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). RESULTS: DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10-8), we identified two differentially methylated positions (DMPs) associated with PUFA intake in the KORA study. The DMP cg19937480, annotated to gene PRDX1, was positively associated with docosahexaenoic acid (DHA) in model 1 (beta: 2.00 × 10-5, 95%CI: 1.28 × 10-5-2.73 × 10-5, P value: 6.98 × 10-8), while cg05041783, annotated to gene MARK2, was positively associated with docosapentaenoic acid (DPA) in our fully adjusted model (beta: 9.80 × 10-5, 95%CI: 6.25 × 10-5-1.33 × 10-4, P value: 6.75 × 10-8). In the meta-analysis, we identified the CpG site (cg15951061), annotated to gene CDCA7L below Bonferroni correction (1.23 × 10-7) associated with eicosapentaenoic acid (EPA) intake in model 1 (beta: 2.00 × 10-5, 95% CI: 1.27 × 10-5-2.73 × 10-5, P value = 5.99 × 10-8) and we confirmed the association of cg19937480 with DHA in both models 1 and 2 (beta: 2.07 × 10-5, 95% CI: 1.31 × 10-5-2.83 × 10-5, P value = 1.00 × 10-7 and beta: 2.19 × 10-5, 95% CI: 1.41 × 10-5-2.97 × 10-5, P value = 5.91 × 10-8 respectively). CONCLUSIONS: Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes.
AU  - Lange de Luna, J.
AU  - Nounu, A.
AU  - Neumeyer, S.
AU  - Sinke, L.*
AU  - Wilson, R.
AU  - Hellbach, F.*
AU  - Matias-Garcia, P.R.
AU  - Delerue, T.
AU  - Winkelmann, J.
AU  - Peters, A.
AU  - Thorand, B.
AU  - Beekman, M.*
AU  - Heijmans, B.T.*
AU  - Slagboom, E.*
AU  - Gieger, C.
AU  - Linseisen, J.*
AU  - Waldenberger, M.
C1  - 69975
C2  - 55218
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Epigenome-wide association study of dietary fatty acid intake.
JO  - Clin. Epigenet.
VL  - 16
IS  - 1
PB  - Bmc
PY  - 2024
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Transportation noise has been linked with breast cancer, but existing literature is conflicting. One proposed mechanism is that transportation noise disrupts sleep and the circadian rhythm. We investigated the relationships between road traffic noise, DNA methylation in circadian rhythm genes, and breast cancer. We selected 610 female participants (318 breast cancer cases and 292 controls) enrolled into the Malmö, Diet, and Cancer cohort. DNA methylation of CpGs (N = 29) in regulatory regions of circadian rhythm genes (CRY1, BMAL1, CLOCK, and PER1) was assessed by pyrosequencing of DNA from lymphocytes collected at enrollment. To assess associations between modeled 5-year mean residential road traffic noise and differentially methylated CpG positions, we used linear regression models adjusting for potential confounders, including sociodemographics, shiftwork, and air pollution. Linear mixed effects models were used to evaluate road traffic noise and differentially methylated regions. Unconditional logistic regression was used to investigate CpG methylation and breast cancer. RESULTS: We found that higher mean road traffic noise was associated with lower DNA methylation of three CRY1 CpGs (CpG1, CpG2, and CpG12) and three BMAL1 CpGs (CpG2, CpG6, and CpG7). Road traffic noise was also associated with differential methylation of CRY1 and BMAL1 promoters. In CRY1 CpG2 and CpG5 and in CLOCK CpG1, increasing levels of methylation tended to be associated with lower odds of breast cancer, with odds ratios (OR) of 0.88 (95% confidence interval (CI) 0.76-1.02), 0.84 (95% CI 0.74-0.96), and 0.80 (95% CI 0.68-0.94), respectively. CONCLUSIONS: In summary, our data suggest that DNA hypomethylation in CRY1 and BMAL1 could be part of a causal chain from road traffic noise to breast cancer. This is consistent with the hypothesis that disruption of the circadian rhythm, e.g., from road traffic noise exposure, increases the risk of breast cancer. Since no prior studies have explored this association, it is essential to replicate our results.
AU  - Thacher, J.D.*
AU  - Snigireva, A.*
AU  - Dauter, U.M.*
AU  - Delaval, M.N.
AU  - Oudin, A.*
AU  - Mattisson, K.*
AU  - Sørensen, M.*
AU  - Borgquist, S.*
AU  - Albin, M.*
AU  - Broberg, K.*
C1  - 72531
C2  - 56641
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Road traffic noise and breast cancer: DNA methylation in four core circadian genes.
JO  - Clin. Epigenet.
VL  - 16
IS  - 1
PB  - Bmc
PY  - 2024
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants. RESULTS: Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p < 0.05), of which 7 metabolites were available in both cohorts and tested for epigenome-wide association. Three metabolites - pipecolate (metabolomic biomarker of B6 and folate intakes), pyridoxate (marker of B6 and folate) and docosahexaenoate (DHA, marker of B6) - were associated with 10, 3 and 1 differentially methylated positions (DMPs), respectively. The strongest association was observed between DHA and DMP cg03440556 in the SCD gene (effect = 0.093 ± 0.016, p = 4.07E-09). Pyridoxate, a catabolic product of vitamin B6, was inversely associated with CpG methylation near the SLC1A5 gene promoter region (cg02711608 and cg22304262) and with SLC7A11 (cg06690548), but not with corresponding changes in gene expression levels. The self-reported intake of folate and vitamin B6 had consistent but non-significant associations with the epigenetic signals. CONCLUSION: Metabolomic biomarkers are a valuable approach to investigate the effects of dietary B vitamin intake on the human epigenome.
AU  - Costeira, R.*
AU  - Evangelista, L.*
AU  - Wilson, R.
AU  - Yan, X.*
AU  - Hellbach, F.*
AU  - Sinke, L.*
AU  - Christiansen, C.*
AU  - Villicaña, S.*
AU  - Masachs, O.M.*
AU  - Tsai, P.C.*
AU  - Mangino, M.*
AU  - Menni, C.*
AU  - Berry, S.E.*
AU  - Beekman, M.*
AU  - van Heemst, D.*
AU  - Slagboom, P.E.*
AU  - Heijmans, B.T.*
AU  - Suhre, K.*
AU  - Kastenmüller, G.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Small, K.S.*
AU  - Linseisen, J.*
AU  - Waldenberger, M.
AU  - Bell, J.T.*
C1  - 68715
C2  - 54924
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Metabolomic biomarkers of habitual B vitamin intakes unveil novel differentially methylated positions in the human epigenome.
JO  - Clin. Epigenet.
VL  - 15
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy. RESULTS: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10 and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. CONCLUSIONS: Our findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.
AU  - Feil, D.*
AU  - Abrishamcar, S.*
AU  - Christensen, G.M.*
AU  - Vanker, A.*
AU  - Koen, N.*
AU  - Kilanowski, A.
AU  - Hoffman, N.*
AU  - Wedderburn, C.J.*
AU  - Donald, K.A.*
AU  - Kobor, M.S.*
AU  - Zar, H.J.*
AU  - Stein, D.J.*
AU  - Hüls, A.*
C1  - 67573
C2  - 54075
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort.
JO  - Clin. Epigenet.
VL  - 15
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: The neuropeptide oxytocin (OXT) plays a role in the regulation of eating behavior and metabolism. OXT functioning is altered in patients with eating and weight disorders, and a variant of the oxytocin receptor gene (OXTR) has been associated with impulsive eating behavior as it is seen in patients with binge eating disorder (BED). Gene × environment interactions could play a role in BED. One mechanism mediating this interaction is the epigenetic alteration of gene expression. We therefore investigated if DNA methylation of the OXTR differs between individuals with obesity depending on a comorbid BED. We analyzed DNA methylation of the OXTR in peripheral blood of 227 individuals on the obesity spectrum (mean age: 40.3 ± 13.1 yrs; mean BMI: 38.6 ± 7.3 kg/m2), 130 of which were diagnosed with BED. RESULTS: There were no overall differences in OXTR methylation between participants with and those without BED (p > 0.05), while both subgroups were comparable regarding age and body mass index (BMI), but significantly differed in sex distribution (p = 0.035). We found no relationship between mean DNA methylation and BMI or self-reported eating disorder (ED) pathology. Analyzing potential sex differences revealed a significantly lower OXTR DNA methylation in male participants with BED as compared to those without BED (p = 0.017). No such difference was found in the female subsample (p > 0.05). CONCLUSIONS: Clinically significant binge eating pathology might be associated with lower OXTR DNA methylation exclusively in males. The differential DNA methylation of OXTR in males with BED supports the view that BED represents a phenotype within the obesity spectrum that is characterized by specific vulnerability factors. A better understanding of the epigenetic underpinnings of the OXT system might contribute to the refinement of OXT administration approaches as potential interventions in eating and weight disorders.
AU  - Giel, K.E.*
AU  - Schag, K.*
AU  - Leehr, E.J.*
AU  - Mack, I.*
AU  - Schuster, L.S.*
AU  - Wiegand, A.*
AU  - Zipfel, S.*
AU  - Hallschmid, M.
AU  - Nieratschker, V.*
C1  - 66067
C2  - 53082
TI  - OXTR DNA methylation differentiates men on the obesity spectrum with and without binge eating disorder.
JO  - Clin. Epigenet.
VL  - 14
IS  - 1
PY  - 2022
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: DNA methylation (DNAm) is considered a plausible pathway through which genetic and environmental factors may influence the development of allergies. However, causality has yet to be determined as it is unknown whether DNAm is rather a cause or consequence of allergic sensitization. Here, we investigated the direction of the observed associations between well-known environmental and genetic determinants of allergy, DNAm, and aeroallergen sensitization using a combination of high-dimensional and causal mediation analyses. Methods: Using prospectively collected data from the German LISA birth cohort from two time windows (6–10 years: N = 234; 10–15 years: N = 167), we tested whether DNAm is a cause or a consequence of aeroallergen sensitization (specific immunoglobulin E > 0.35kU/l) by conducting mediation analyses for both effect directions using maternal smoking during pregnancy, family history of allergies, and a polygenic risk score (PRS) for any allergic disease as exposure variables. We evaluated individual CpG sites (EPIC BeadChip) and allergy-related methylation risk scores (MRS) as potential mediators in the mediation analyses. We applied three high-dimensional mediation approaches (HIMA, DACT, gHMA) and validated results using causal mediation analyses. A replication of results was attempted in the Swedish BAMSE cohort. Results: Using high-dimensional methods, we identified five CpGs as mediators of prenatal exposures to sensitization with significant (adjusted p < 0.05) indirect effects in the causal mediation analysis (maternal smoking: two CpGs, family history: one, PRS: two). None of these CpGs could be replicated in BAMSE. The effect of family history on allergy-related MRS was significantly mediated by aeroallergen sensitization (proportions mediated: 33.7–49.6%), suggesting changes in DNAm occurred post-sensitization. Conclusion: The results indicate that DNAm may be a cause or consequence of aeroallergen sensitization depending on genomic location. Allergy-related MRS, identified as a potential cause of sensitization, can be considered as a cross-sectional biomarker of disease. Differential DNAm in individual CpGs, identified as mediators of the development of sensitization, could be used as clinical predictors of disease development.
AU  - Kilanowski, A.
AU  - Merid, S.K.*
AU  - Abrishamcar, S.*
AU  - Feil, D.*
AU  - Thiering, E.
AU  - Waldenberger, M.
AU  - Melén, E.*
AU  - Peters, A.
AU  - Standl, M.
AU  - Hüls, A.*
C1  - 66214
C2  - 52763
TI  - DNA methylation and aeroallergen sensitization: The chicken or the egg?
JO  - Clin. Epigenet.
VL  - 14
IS  - 1
PY  - 2022
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. Methods: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4–13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. Results: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10–8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10–8, n = 577) and sleep onset latency (p = 8.8 × 10–9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716–2539). Conclusion: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.
AU  - Sammallahti, S.*
AU  - Koopman-Verhoeff, M.E.*
AU  - Binter, A.C.*
AU  - Mulder, R.H.*
AU  - Cabré-Riera, A.*
AU  - Kvist, T.*
AU  - Malmberg, A.L.K.*
AU  - Pesce, G.*
AU  - Plancoulaine, S.*
AU  - Heiss, J.A.*
AU  - Rifas-Shiman, S.L.*
AU  - Röder, S.W.*
AU  - Starling, A.P.*
AU  - Wilson, R.
AU  - Guerlich, K.*
AU  - Haftorn, K.L.*
AU  - Page, C.M.*
AU  - Luik, A.I.*
AU  - Tiemeier, H.*
AU  - Felix, J.F.*
AU  - Räikkönen, K.*
AU  - Lahti, J.*
AU  - Relton, C.L.*
AU  - Sharp, G.C.*
AU  - Waldenberger, M.
AU  - Grote, V.*
AU  - Heude, B.*
AU  - Annesi-Maesano, I.*
AU  - Hivert, M.F.*
AU  - Zenclussen, A.C.*
AU  - Herberth, G.*
AU  - Dabelea, D.*
AU  - Grazuleviciene, R.*
AU  - Vafeiadi, M.*
AU  - Håberg, S.E.*
AU  - London, S.J.*
AU  - Guxens, M.*
AU  - Richmond, R.C.*
AU  - Cecil, C.A.M.*
C1  - 65623
C2  - 52543
TI  - Longitudinal associations of DNA methylation and sleep in children: A meta-analysis.
JO  - Clin. Epigenet.
VL  - 14
IS  - 1
PY  - 2022
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant's neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA. RESULTS: A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a 'Fetal Stress Index' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn's saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D. CONCLUSIONS: Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.
AU  - Sharma, R.
AU  - Frasch, M.G.*
AU  - Zelgert, C.*
AU  - Zimmermann, P.*
AU  - Fabre, B.*
AU  - Wilson, R.
AU  - Waldenberger, M.
AU  - MacDonald, J.W.*
AU  - Bammler, T.K.*
AU  - Lobmaier, S.M.*
AU  - Antonelli, M.C.*
C1  - 65698
C2  - 52461
TI  - Maternal-fetal stress and DNA methylation signatures in neonatal saliva: An epigenome-wide association study.
JO  - Clin. Epigenet.
VL  - 14
IS  - 1
PY  - 2022
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. Methods: We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. Results: EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change. Conclusion: Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.
AU  - Chen, Y.*
AU  - Kassam, I.*
AU  - Lau, S.H.*
AU  - Kooner, J.S.*
AU  - Wilson, R.
AU  - Peters, A.
AU  - Winkelmann, J.
AU  - Chow, V.T.*
AU  - Khor, C.C.*
AU  - van Dam, R.M.*
AU  - Teo, Y.Y.*
AU  - Loh, M.*
AU  - Sim, X.*
C1  - 63354
C2  - 51344
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: An EWAS in multi-ethnic Asian individuals.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
AU  - Gomez Alonso, M.D.C.
AU  - Kretschmer, A.
AU  - Wilson, R.
AU  - Pfeiffer, L.
AU  - Karhunen, V.*
AU  - Seppälä, I.*
AU  - Zhang, W.*
AU  - Mittelstraß, K.
AU  - Wahl, S.
AU  - Matias-Garcia, P.R.
AU  - Prokisch, H.
AU  - Horn, S.
AU  - Meitinger, T.
AU  - Serrano Garcia, L.R.
AU  - Sebert, S.*
AU  - Raitakari, O.*
AU  - Loh, M.*
AU  - Rathmann, W.*
AU  - Müller-Nurasyid, M.
AU  - Herder, C.*
AU  - Roden, M.*
AU  - Hurme, M.*
AU  - Jarvelin, M.R.*
AU  - Ala-Korpela, M.*
AU  - Kooner, J.S.*
AU  - Peters, A.
AU  - Lehtimäki, T.*
AU  - Gieger, C.
AU  - Kettunen, J.*
AU  - Waldenberger, M.
C1  - 60930
C2  - 49813
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - DNA methylation and lipid metabolism: An EWAS of 226 metabolic measures.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results: By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61–0.66 in the external validation datasets. Conclusions: The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.
AU  - Maas, S.C.E.*
AU  - Vidaki, A.*
AU  - Teumer, A.*
AU  - Costeira, R.*
AU  - Wilson, R.
AU  - van Dongen, J.*
AU  - Beekman, M.*
AU  - Völker, U.*
AU  - Grabe, H.J.*
AU  - Kunze, S.
AU  - Ladwig, K.-H.
AU  - van Meurs, J.B.J.*
AU  - Uitterlinden, A.G.*
AU  - Voortman, T.*
AU  - Boomsma, D.I.*
AU  - Slagboom, P.E.*
AU  - van Heemst, D.*
AU  - van der Kallen, C.J.H.*
AU  - van den Berg, L.H.*
AU  - Waldenberger, M.
AU  - Völzke, H.*
AU  - Peters, A.
AU  - Bell, J.T.*
AU  - Ikram, M.A.*
AU  - Ghanbari, M.*
AU  - Kayser, M.*
C1  - 63391
C2  - 51522
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Validating biomarkers and models for epigenetic inference of alcohol consumption from blood.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. RESULTS: We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. CONCLUSIONS: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.
AU  - Marttila, S.*
AU  - Viiri, L.E.*
AU  - Mishra, P.P.*
AU  - Kühnel, B.
AU  - Matias-Garcia, P.R.
AU  - Lyytikäinen, L.P.*
AU  - Ceder, T.*
AU  - Mononen, N.*
AU  - Rathmann, W.*
AU  - Winkelmann, J.
AU  - Peters, A.
AU  - Kähönen, M.*
AU  - Hutri-Kähönen, N.*
AU  - Juonala, M.*
AU  - Aalto-Setälä, K.*
AU  - Raitakari, O.*
AU  - Lehtimäki, T.*
AU  - Waldenberger, M.
AU  - Raitoharju, E.*
C1  - 62628
C2  - 50965
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
AU  - Matias-Garcia, P.R.
AU  - Ward-Caviness, C.K.*
AU  - Raffield, L.M.*
AU  - Gao, X.*
AU  - Zhang, Y.*
AU  - Wilson, R.
AU  - Nano, J.
AU  - Bostom, A.*
AU  - Colicino, E.*
AU  - Correa, A.*
AU  - Coull, B.*
AU  - Eaton, C.*
AU  - Hou, L.*
AU  - Just, A.C.*
AU  - Kunze, S.
AU  - Lange, L.*
AU  - Lange, E.M.*
AU  - Lin, X.*
AU  - Liu, S.*
AU  - Nwanaji-Enwerem, J.C.*
AU  - Reiner, A.*
AU  - Shen, J.*
AU  - Schöttker, B.*
AU  - Vokonas, P.*
AU  - Zheng, Y.*
AU  - Young, B.*
AU  - Schwartz, J.*
AU  - Horvath, S.*
AU  - Lu, A.*
AU  - Whitsel, E.A.*
AU  - Koenig, W.*
AU  - Adamski, J.
AU  - Winkelmann, J.
AU  - Brenner, H.*
AU  - Baccarelli, A.A.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Franceschini, N.*
AU  - Waldenberger, M.
C1  - 62207
C2  - 49911
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. RESULTS: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. CONCLUSIONS: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
AU  - Yao, C.*
AU  - Joehanes, R.*
AU  - Wilson, R.
AU  - Tanaka, T.*
AU  - Ferrucci, L.*
AU  - Kretschmer, A.
AU  - Prokisch, H.
AU  - Schramm, K.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Waldenberger, M.
AU  - Marzi, C.
AU  - Herder, C.*
AU  - Levy, D.*
C1  - 61698
C2  - 50165
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (∆mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets. RESULTS: Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10-53). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10-55). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( ∆ = 0.6 years vs. ∆ = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (∆ = 0.6 years vs. ∆ = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05). CONCLUSIONS: Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724 .
AU  - Yaskolka Meir, A.*
AU  - Keller, M.
AU  - Bernhart, S.H.*
AU  - Rinott, E.*
AU  - Tsaban, G.*
AU  - Zelicha, H.*
AU  - Kaplan, A.*
AU  - Schwarzfuchs, D.*
AU  - Shelef, I.*
AU  - Gepner, Y.*
AU  - Li, J.*
AU  - Lin, Y.*
AU  - Blüher, M.
AU  - Ceglarek, U.*
AU  - Stumvoll, M.
AU  - Stampfer, M.J.*
AU  - Kovacs, P.*
AU  - Liang, L.*
AU  - Shai, I.*
C1  - 61451
C2  - 50258
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Lifestyle weight-loss intervention may attenuate methylation aging: The CENTRAL MRI randomized controlled trial.
JO  - Clin. Epigenet.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. Results We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.
AU  - Maas, S.C.E.*
AU  - Mens, M.M.J.*
AU  - Kühnel, B.
AU  - van Meurs, J.B.J.*
AU  - Uitterlinden, A.G.*
AU  - Peters, A.
AU  - Prokisch, H.
AU  - Herder, C.*
AU  - Grallert, H.
AU  - Kunze, S.
AU  - Waldenberger, M.
AU  - Kavousi, M.*
AU  - Kayser, M.*
AU  - Ghanbari, M.*
C1  - 60385
C2  - 49270
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits.
JO  - Clin. Epigenet.
VL  - 12
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BackgroundEpigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported.ResultsWe repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1h, 3h, 6h), which returned to baseline levels within 23h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS.ConclusionOur study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.
AU  - Wiechmann, T.*
AU  - Röh, S.*
AU  - Sauer, S.*
AU  - Czamara, D.*
AU  - Knauer-Arloth, J.
AU  - Ködel, M.*
AU  - Beintner, M.*
AU  - Knop, L.*
AU  - Menke, A.*
AU  - Binder, E.B.*
AU  - Provençal, N.*
C1  - 56172
C2  - 46862
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus.
JO  - Clin. Epigenet.
VL  - 11
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.
AU  - Beck, A.*
AU  - Trippel, F.*
AU  - Wagner, A.*
AU  - Joppien, S.*
AU  - Felle, M.*
AU  - Vokuhl, C.*
AU  - Schwarzmayr, T.
AU  - Strom, T.M.
AU  - von Schweinitz, D.*
AU  - Längst, G.*
AU  - Kappler, R.*
C1  - 53232
C2  - 44649
CY  - London
TI  - Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.
JO  - Clin. Epigenet.
VL  - 10
IS  - 1
PB  - Biomed Central Ltd
PY  - 2018
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BackgroundMost research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics.ResultsUsing paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an epigenetic fingerprint of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC=0.61, P=6.5x10(-3)). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism.ConclusionsThere are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.
AU  - Ward-Caviness, C.K.
AU  - Agha, G.*
AU  - Chen, B.H.*
AU  - Pfeiffer, L.
AU  - Wilson, R.
AU  - Wolf, P.
AU  - Gieger, C.
AU  - Schwartz, J.*
AU  - Vokonas, P.S.*
AU  - Hou, L.*
AU  - Just, A.C.*
AU  - Bandinelli, S.*
AU  - Hernandez, D.G.*
AU  - Singleton, A.B.*
AU  - Prokisch, H.
AU  - Meitinger, T.
AU  - Kastenmüller, G.
AU  - Ferrucci, L.*
AU  - Baccarelli, A.A.*
AU  - Waldenberger, M.
AU  - Peters, A.
C1  - 55066
C2  - 46035
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction.
JO  - Clin. Epigenet.
VL  - 10
IS  - 1
PB  - Bmc
PY  - 2018
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: The prevalence of type 2 diabetes (T2D) and obesity has dramatically increased within a few generations, reaching epidemic levels. In addition to genetic risk factors, epigenetic mechanisms triggered by changing environment are investigated for their role in the pathogenesis of these complex diseases. Epigenome-wide association studies (EWASs) have revealed significant associations of T2D, obesity, and BMI with DNA methylation. However, populations from the Middle East, where T2D and obesity rates are highest worldwide, have not been investigated so far. METHODS: We performed the first EWAS in an Arab population with T2D and BMI and attempted to replicate 47 EWAS associations previously reported in Caucasians. We used the Illumina Infinium HumanMethylation450 BeadChip to quantify DNA methylation in whole blood DNA from 123 subjects of 15 multigenerational families from Qatar. To investigate the effect of differing genetic background and environment on the epigenetic associations, we further assessed the effect of replicated loci in 810 twins from UK. RESULTS: Our EWAS suggested a novel association between T2D and cg06721411 (DQX1; p value = 1.18 × 10(-9)). We replicated in the Qatari population seven CpG associations with BMI (SOCS3, p value = 3.99 × 10(-6); SREBF1, p value = 4.33 × 10(-5); SBNO2, p value = 5.87 × 10(-5); CPT1A, p value = 7.99 × 10(-5); PRR5L, p value = 1.85 × 10(-4); cg03078551, intergenic region on chromosome 17; p value = 1.00 × 10(-3); LY6G6E, p value = 1.10 × 10(-3)) and one with T2D (TXNIP, p value = 2.46 × 10(-5)). All the associations were further confirmed in the UK cohort for both BMI and T2D. Meta-analysis increased the significance of the observed associations and revealed strong heterogeneity of the effect sizes (apart from CPT1A), although associations at these loci showed concordant direction in the two populations. CONCLUSIONS: Our study replicated eight known CpG associations with T2D or BMI in an Arab population. Heterogeneity of the effects at all loci except CPT1A between the Qatari and UK studies suggests that the underlying mechanisms might depend on genetic background and environmental pressure. Our EWAS results provide a basis for comparison with other ethnicities.
AU  - Al Muftah, W.A.*
AU  - Al-Shafai, M.*
AU  - Zaghlool, S.B.*
AU  - Visconti, A.*
AU  - Tsai, P.C.*
AU  - Kumar, P.*
AU  - Spector, T.*
AU  - Bell, J.*
AU  - Falchi, M.*
AU  - Suhre, K.
C1  - 47786
C2  - 39478
CY  - London
TI  - Epigenetic associations of type 2 diabetes and BMI in an Arab population.
JO  - Clin. Epigenet.
VL  - 8
PB  - Biomed Central Ltd
PY  - 2016
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Background: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such “heritable” CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian. Methods: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes. Results: We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/−110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/−1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site. Conclusions: Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10−6), implying a regulatory effect of these trimodal CpG sites.
AU  - Zaghlool, S.B.*
AU  - Al-Shafai, M.*
AU  - Al Muftah, W.A.*
AU  - Kumar, P.*
AU  - Gieger, C.
AU  - Waldenberger, M.
AU  - Falchi, M.*
AU  - Suhre, K.*
C1  - 50049
C2  - 40885
CY  - London
TI  - Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects.
JO  - Clin. Epigenet.
VL  - 8
PB  - Biomed Central Ltd
PY  - 2016
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - Evidence is now emerging that early life environment can have lifelong effects on metabolic, cardiovascular, and pulmonary function in offspring, a concept also known as fetal or developmental programming. In mammals, developmental programming is thought to occur mainly via epigenetic mechanisms, which include DNA methylation, histone modifications, and expression of non-coding RNAs. The effects of developmental programming can be induced by the intrauterine environment, leading to intergenerational epigenetic effects from one generation to the next. Transgenerational epigenetic inheritance may be considered when developmental programming is transmitted across generations that were not exposed to the initial environment which triggered the change. So far, inter- and transgenerational programming has been mainly described for cardiovascular and metabolic disease risk. In this review, we discuss available evidence that epigenetic inheritance also occurs in respiratory diseases, using asthma and chronic obstructive pulmonary disease (COPD) as examples. While multiple epidemiological as well as animal studies demonstrate effects of 'toxic' intrauterine exposure on various asthma-related phenotypes in the offspring, only few studies link epigenetic marks to the observed phenotypes. As epigenetic marks may distinguish individuals most at risk of later disease at early age, it will enable early intervention strategies to reduce such risks. To achieve this goal further, well designed experimental and human studies are needed.
AU  - Krauss-Etschmann, S.
AU  - Meyer, K.F.*
AU  - Dehmel, S.
AU  - Hylkema, M.N.*
C1  - 45127
C2  - 37248
CY  - London
TI  - Inter- and transgenerational epigenetic inheritance: Evidence in asthma and COPD?
JO  - Clin. Epigenet.
VL  - 7
IS  - 1
PB  - Biomed Central Ltd
PY  - 2015
SN  - 1868-7075
ER  - 

TY  - JOUR
AB  - BACKGROUND: Modification of DNA by methylation of cytosines at CpG dinucleotides is a widespread phenomenon that leads to changes in gene expression, thereby influencing and regulating many biological processes. Recent technical advances in the genome-wide determination of single-base DNA-methylation enabled epigenome-wide association studies (EWASs). Early EWASs established robust associations between age and gender with the degree of CpG methylation at specific sites. Other studies uncovered associations with cigarette smoking. However, so far these studies were mainly conducted in Caucasians, raising the question of whether these findings can also be extrapolated to other populations. RESULTS: Here, we present an EWAS with age, gender, and smoking status in a family study of 123 individuals of Arab descent. We determined DNA methylation at over 450,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip, applied state-of-the-art data processing protocols, including correction for blood cell type heterogeneity and hidden confounders, and eliminated probes containing SNPs at the targeted CpG site using 40× whole-genome sequencing data. Using this approach, we could replicate the leading published EWAS associations with age, gender and smoking, and recovered hallmarks of gender-specific epigenetic changes. Interestingly, we could even replicate the recently reported precise prediction of chronological age based on the methylation of only a few selected CpG sites. CONCLUSION: Our study supports the view that when applied with state-of-the art protocols to account for all potential confounders, DNA methylation arrays represent powerful tools for EWAS with more complex phenotypes that can also be successfully applied to non-Caucasian populations.
AU  - Zaghlool, S.B.*
AU  - Al-Shafai, M.*
AU  - Al Muftah, W.A.*
AU  - Kumar, P.*
AU  - Falchi, M.*
AU  - Suhre, K.
C1  - 43265
C2  - 36373
CY  - London
TI  - Association of DNA methylation with age, gender, and smoking in an Arab population.
JO  - Clin. Epigenet.
VL  - 7
IS  - 1
PB  - Biomed Central Ltd
PY  - 2015
SN  - 1868-7075
ER  -