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      DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

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          Abstract

          DNA methylation mediates the association of prenatal famine exposure with higher adult BMI and serum triglyceride levels.

          Abstract

          Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation.

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          Fitting Linear Mixed-Effects Models Using lme4

          Maximum likelihood or restricted maximum likelihood (REML) estimates of the parameters in linear mixed-effects models can be determined using the lmer function in the lme4 package for R. As for most model-fitting functions in R, the model is described in an lmer call by a formula, in this case including both fixed- and random-effects terms. The formula and data together determine a numerical representation of the model from which the profiled deviance or the profiled REML criterion can be evaluated as a function of some of the model parameters. The appropriate criterion is optimized, using one of the constrained optimization functions in R, to provide the parameter estimates. We describe the structure of the model, the steps in evaluating the profiled deviance or REML criterion, and the structure of classes or types that represents such a model. Sufficient detail is included to allow specialization of these structures by users who wish to write functions to fit specialized linear mixed models, such as models incorporating pedigrees or smoothing splines, that are not easily expressible in the formula language used by lmer. Journal of Statistical Software, 67 (1) ISSN:1548-7660
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            Obesity at the age of 50 y in men and women exposed to famine prenatally.

            It was shown that men who were conceived during the Dutch famine of 1944-1945 had higher rates of obesity at age 19 y than those conceived before or after it. Our objective was to study the effects of prenatal exposure to the Dutch famine on obesity in women and men at age 50 y. We measured the body size of 741 people born at term between November 1943 and February 1947 in Amsterdam. We compared people exposed to famine in late, mid, or early gestation (exposed participants) with those born before or conceived after the famine period (nonexposed participants). The body mass index (BMI; in kg/m(2)) of 50-y-old women exposed to famine in early gestation was significantly higher by 7. 4% (95% CI: 0.7%, 14.5%) than that of nonexposed women. BMI did not differ significantly in women exposed in mid gestation (-2.1%; -7.0%, 3.1%) or in late gestation (-1.3%; -6.3%, 3.9%). In 50-y-old men, BMI was not significantly affected by exposure to famine during any stage of gestation: BMI differed by 0.4% (-3.5%, 4.5%) in men exposed to famine in late gestation, by -1.2% (-5.5%, 3.3%) in those exposed in mid gestation, and by 0.5% (-4.6%, 6.0%) in those exposed in early gestation compared with nonexposed men. Maternal malnutrition during early gestation was associated with higher BMI and waist circumference in 50-y-old women but not in men. These findings suggest that pertubations of central endocrine regulatory systems established in early gestation may contribute to the development of abdominal obesity in later life.
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              Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation

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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                January 2018
                31 January 2018
                : 4
                : 1
                Affiliations
                [1 ]Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
                [2 ]Division of Human Nutrition, Wageningen University and Research, 6708 WE Wageningen, Netherlands.
                [3 ]Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
                [4 ]Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
                [5 ]Faculty of Psychology and Educational Sciences, Welten Institute, Open University of the Netherlands, 6419 AT Heerlen, Netherlands.
                [6 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
                Author notes
                [*]

                The consortium member names are listed in the acknowledgments.

                [†]

                These authors contributed equally to this work.

                []Corresponding author. Email: bas.heijmans@ 123456lumc.nl
                Article
                aao4364
                10.1126/sciadv.aao4364
                5792223
                Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: award340370
                Award ID: R01-HL067914
                Funded by: doi http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: award340369
                Award ID: R01AG042190
                Funded by: doi http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: award340371
                Award ID: 259679
                Funded by: Netherlands Organization for Scientific Research;
                Award ID: award359247
                Award ID: 91617128
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Diseases and Disorders
                Human Genetics
                Human Genetics
                Custom metadata
                Rochelle Abragante

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