Epigenome-wide association study reveals a molecular signature of response to phylloquinone (vitamin K1) supplementation.
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ABSTRACT:
SUBMITTER: Westerman K
PROVIDER: S-EPMC7518702 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThe pharmacokinetics of phylloquinone (vitamin K1) were evaluated in healthy human adult volunteers (15 male and 15 female) following oral and intravenous administration of a mixed micelles formulation (Konakion MM 2 mg) in an open label study design. The subjects were allocated to one of three genotype-specific groups (n = 10 in each group) in terms of VKORC1 promoter polymorphism c.-1639 G > A to explore the relationship between genotype and pharmacokinetic parameters.MethodsBlood samples were collected for up to 24 h after administration. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. Pharmacokinetic evaluation was performed using non-compartmental analysis.ResultsPharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in the main pharmacokinetic parameters between groups. Upon oral administration, VKORC1 AG carriers showed 41 % higher mean bioavailability (p = 0.01) compared with homozygous AA individuals. Furthermore, AG subjects exhibited 30 % (p = 0.042) and 36 % (p = 0.021) higher mean AUC compared with GG and AA respectively. Terminal half-life was 32 % and 27 % longer for AG carriers in comparison to GG (p = 0.004) and AA (p = 0.015) genotypes respectively.ConclusionPharmacokinetic differences indicated significant inter-individual variance of vitamin K fate in the human body. The influence of the VKORC1 promoter polymorphism c.-1639 G > A on the pharmacokinetic properties of phylloquinone could be demonstrated in humans. To gain deeper insight in other potential genetic determinants of systemic vitamin K exposure, further correlation of the phenotype-genotype relationship of different players in vitamin K turnover has to be gained.
| S-EPMC3572390 | biostudies-literature
Project description:Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study.The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K.We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P < 1 × 10(-6) were then evaluated in a second-stage analysis consisting of one independent cohort (n = 265).No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 × 10(-8). However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 × 10(-6), including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes APOA1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P < 0.05).Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
| S-EPMC4232014 | biostudies-literature
Project description:The increase in the prevalence of allergic diseases is believed to partially depend on environmental changes. DNA methylation is a major epigenetic mechanism, which is known to respond to environmental factors. A number of studies have revealed that patterns of DNA methylation may potentially predict allergic diseases.Here, we examined how maternal atopy is associated with methylation patterns in the cord blood of neonates.We conducted an epigenome-wide association study in a cohort of 96 mother-child pairs. Pregnant women aged not more than 35 years old, not currently smoking or exposed to environmental tobacco smoke, who did not report obesity before conception were considered eligible. They were further tested for atopy. Converted DNA from cord blood was analysed using Infinium MethylationEPIC; for statistical analysis, RnBeads software was applied. Gestational age and sex were included as covariates in the final analysis.83 DM sites were associated with maternal atopy. Within the top DM sites, there were CpG sites which mapped to genes SCD, ITM2C, NT5C3A and NPEPL1. Regional analysis revealed 25 tiling regions, 4 genes, 3 CpG islands and 5 gene promoters, (including PIGCP1, ADAM3A, ZSCAN12P1) associated with maternal atopy. Gene content analysis revealed pointwise enrichments in pathways related to purine-containing compound metabolism, the G1/S transition of the mitotic cell cycle, stem cell division and cellular glucose homoeostasis.These findings suggest that maternal atopy provides a unique intrauterine environment that may constitute the first environment in which exposure is associated with methylation patterns in newborn.
| S-EPMC8143219 | biostudies-literature
Project description:Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.
| S-EPMC6557548 | biostudies-literature
Project description:We conducted an epigenome-wide association study on obesity-related traits. We used data from 2 prospective, population-based cohort studies: the Rotterdam Study (RS) (2006-2013) and the Atherosclerosis Risk in Communities (ARIC) Study (1990-1992). We used the RS (n = 1,450) as the discovery panel and the ARIC Study (n = 2,097) as the replication panel. Linear mixed-effect models were used to assess the cross-sectional associations between genome-wide DNA methylation in leukocytes and body mass index (BMI) and waist circumference (WC), adjusting for sex, age, smoking, leukocyte proportions, array number, and position on array. The latter 2 variables were modeled as random effects. Fourteen 5'-C-phosphate-G-3' (CpG) sites were associated with BMI and 26 CpG sites with WC in the RS after Bonferroni correction (P < 1.07 × 10-7), of which 12 and 13 CpGs were replicated in the ARIC Study, respectively. The most significant novel CpGs were located on the Musashi RNA binding protein 2 gene (MSI2; cg21139312) and the leucyl-tRNA synthetase 2, mitochondrial gene (LARS2; cg18030453) and were associated with both BMI and WC. CpGs at BRDT, PSMD1, IFI44L, MAP1A, and MAP3K5 were associated with BMI. CpGs at LGALS3BP, MAP2K3, DHCR24, CPSF4L, and TMEM49 were associated with WC. We report novel associations between methylation at MSI2 and LARS2 and obesity-related traits. These results provide further insight into mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases.
| S-EPMC6070087 | biostudies-other
Project description:DNA methylation, the most intensively studied epigenetic modification, plays an important role in understanding the molecular basis of diseases. Furthermore, epigenome-wide association study (EWAS) provides a systematic approach to identify epigenetic variants underlying common diseases/phenotypes. However, there is no comprehensive database to archive the results of EWASs. To fill this gap, we developed the EWASdb, which is a part of 'The EWAS Project', to store the epigenetic association results of DNA methylation from EWASs. In its current version (v 1.0, up to July 2018), the EWASdb has curated 1319 EWASs associated with 302 diseases/phenotypes. There are three types of EWAS results curated in this database: (i) EWAS for single marker; (ii) EWAS for KEGG pathway and (iii) EWAS for GO (Gene Ontology) category. As the first comprehensive EWAS database, EWASdb has been searched or downloaded by researchers from 43 countries to date. We believe that EWASdb will become a valuable resource and significantly contribute to the epigenetic research of diseases/phenotypes and have potential clinical applications. EWASdb is freely available at http://www.ewas.org.cn/ewasdb or http://www.bioapp.org/ewasdb.
| S-EPMC6323898 | biostudies-literature
Project description:BackgroundIn DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for statistical analysis: Beta-values and M-values. M-values follow a normal distribution and help to detect differentially methylated CpG sites. As biological effect measures, differences of M-values are more or less meaningless. Beta-values are of more interest since they can be interpreted directly as differences in percentage of DNA methylation at a given CpG site, but they have poor statistical properties. Different frameworks are proposed for reporting estimands in DNA methylation analysis, relying on Beta-values, M-values, or both.ResultsWe present and discuss four possible approaches of achieving estimands in DNA methylation analysis. In addition, we present the usage of M-values or Beta-values in the context of bioinformatical pipelines, which often demand a predefined outcome. We show the dependencies between the differences in M-values to differences in Beta-values in two data simulations: a analysis with and without confounder effect. Without present confounder effects, M-values can be used for the statistical analysis and Beta-values statistics for the reporting. If confounder effects exist, we demonstrate the deviations and correct the effects by the intercept method. Finally, we demonstrate the theoretical problem on two large human genome-wide DNA methylation datasets to verify the results.ConclusionsThe usage of M-values in the analysis of DNA methylation data will produce effect estimates, which cannot be biologically interpreted. The parallel usage of Beta-value statistics ignores possible confounder effects and can therefore not be recommended. Hence, if the differences in Beta-values are the focus of the study, the intercept method is recommendable. Hyper- or hypomethylated CpG sites must then be carefully evaluated. If an exploratory analysis of possible CpG sites is the aim of the study, M-values can be used for inference.
| S-EPMC8086103 | biostudies-literature
Project description:BackgroundInterest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation.ResultsIn EPIC, we found that high epigenome-wide methylation was associated with lower risk of breast cancer (odds ratio (OR) per 1 SD = 0.61, 95 % confidence interval (CI) 0.47-0.80; -0.2 % average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR = 0.51, 95 % CI 0.38-0.69) but not in gene promoters (OR = 0.92, 95 % CI 0.64-1.32). The association was not replicated in NOWAC (OR = 1.03 95 % CI 0.81-1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools = -0.2 %).ConclusionsWe conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker.
| S-EPMC4524428 | biostudies-literature
Project description:BackgroundIt is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer.MethodsAn estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs.ResultsWe observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts.ConclusionWe have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.
| S-EPMC6492393 | biostudies-literature
Project description:BackgroundUnder-γ-carboxylated osteocalcin (ucOC) increases insulin secretion and decreases glucose concentrations in mice.ObjectiveWe determined whether changes in ucOC concentrations in humans were associated with changes in insulin and glucose concentrations.DesignTwenty-one community-dwelling postmenopausal women received 1 mg phylloquinone daily for 12 mo (experimental group), and 21 subjects were treated with a placebo during the same period (control group). Total serum osteocalcin, ucOC, glucose, and insulin concentrations were measured before and 6 and 12 mo after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated and correlated with ucOC concentrations.ResultsBefore administration of the placebo or phylloquinone, total osteocalcin, ucOC, glucose, and insulin concentrations and HOMA-IR (1.24 ± 0.15 for the control group compared with 1.93 ± 0.37 for the experimental group) did not differ. After treatment, total osteocalcin concentrations were similar at 6 and 12 mo. At 6 mo, serum ucOC concentrations in the experimental group were 0.96 ± 0.08 ng/mL compared with 2.94 ± 0.27 ng/mL in the control group (P < 0.001). At 12 mo, serum ucOC concentrations were 0.92 ± 0.09 ng/mL and 3.13 ± 0.26 ng/mL (P < 0.001) in experimental and control groups, respectively. Despite a decrease of ≈200% in ucOC concentrations, HOMA-IR was similar in the 2 groups at 6 and 12 mo (at 6 mo, HOMA-IR was 2.24 ± 0.54 and 1.52 ± 0.23 in the experimental and control groups, respectively; at 12 mo, HOMA-IR was 2.13 ± 0.38 and 1.47 ± 0.22 in the experimental and control groups, respectively; P = NS).ConclusionsIn postmenopausal women, phylloquinone administration is not associated with changes in insulin secretion and action despite reductions in ucOC concentrations. Changes in ucOC concentrations do not alter glucose metabolism in women. This trial was registered at clinicaltrials.gov as NCT00062595.
| S-EPMC2980972 | biostudies-literature