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Research Paper

Alterations in DNA methylation associate with fatty liver and metabolic abnormalities in a multi-ethnic cohort of pre-teenage children

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Pages 1446-1461 | Received 03 Sep 2021, Accepted 01 Feb 2022, Published online: 21 Feb 2022

References

  • Sahota AK, Shapiro WL, Newton KP, et al. Incidence of Nonalcoholic Fatty Liver Disease in Children: 2009-2018. Pediatrics. 2020;146(6). DOI:10.1542/peds.2020-0771
  • Temple JL, Cordero P, Li J, et al. A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence. Int J Mol Sci. 2016;17(6):947.
  • Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–1393.
  • Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319–334.
  • Nobili V, Alisi A, Newton KP, et al. Comparison of the Phenotype and Approach to Pediatric vs Adult Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2016;150(8):1798–1810.
  • Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20.
  • Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–1544.
  • Holterman A-XL, Guzman G, Fantuzzi G, et al. Nonalcoholic fatty liver disease in severely obese adolescent and adult patients. Obesity (Silver Spring). 2013;21(3):591–597.
  • Vittorio J, Lavine JE. Recent advances in understanding and managing pediatric nonalcoholic fatty liver disease. F1000Research. 2020;9:377.
  • Ayonrinde OT, Adams LA, Mori TA, et al. Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents. Hepatology. 2018;67(1):108–122.
  • Ayonrinde OT, Oddy WH, Adams LA, et al. Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents. J Hepatol. 2017;67(3):568–576.
  • Brumbaugh DE, Tearse P, Cree-Green M, et al. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr. 2013;162(5):930–936 e931.
  • Modi N, Murgasova D, Ruager-Martin R, et al. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr Res. 2011;70(3):287–291.
  • Patel KR, White FV, Deutsch GH. Hepatic steatosis is prevalent in stillborns delivered to women with diabetes mellitus. J Pediatr Gastroenterol Nutr. 2015;60(2):152–158.
  • Newton KP, Feldman HS, Chambers CD, et al. Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children. J Pediatr. 2017;187:141–146 e141.
  • Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114(2):147–152.
  • Angulo P. Obesity and nonalcoholic fatty liver disease. Nutr Rev. 2007;65(6 Pt 2):S57–63.
  • Xanthakos SA, Lavine JE, Yates KP, et al. Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice. Gastroenterology. 2020;159(5):1731–1751. e1710.
  • Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–398.
  • Sharp GC, Salas LA, Monnereau C, et al. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Hum Mol Genet. 2017;26(20):4067–4085.
  • Martin CL, Jima D, Sharp GC, et al. Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study. Epigenetics. 2019;14(4):325–340.
  • Girchenko P, Lahti J, Czamara D, et al. Associations between maternal risk factors of adverse pregnancy and birth outcomes and the offspring epigenetic clock of gestational age at birth. Clin Epigenetics. 2017;9(1):49.
  • Czamara D, Eraslan G, Page CM, et al. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. Nat Commun. 2019;10(1):2548.
  • Murphy SK, Yang H, Moylan CA, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145(5):1076–1087.
  • Hotta K, Kitamoto A, Kitamoto T, et al. Identification of differentially methylated region (DMR) networks associated with progression of nonalcoholic fatty liver disease. Sci Rep. 2018;8(1):13567.
  • Gerhard GS, Malenica I, Llaci L, et al. Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways. Clin Epigenetics. 2018;10(1):93.
  • Ahrens M, Ammerpohl O, von Schonfels W, et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013;18(2):296–302.
  • Ma J, Nano J, Ding J, et al. A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease. Diabetes. 2019;68(5):1073–1083.
  • Hardy T, Zeybel M, Day CP, et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut. 2017;66(7):1321–1328.
  • Geurtsen ML, Jaddoe VWV, Salas LA, et al. Newborn and childhood differential DNA methylation and liver fat in school-age children. Clin Epigenetics. 2019;12(1):3.
  • Slieker RC, Bos SD, Goeman JJ, et al. Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array. Epigenetics Chromatin. 2013;6(1):26.
  • Johnson ND, Wu X, Still CD, et al. Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clin Epigenetics. 2021;13(1):152.
  • Nano J, Ghanbari M, Wang W, et al. Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis. Gastroenterology. 2017;153(4):1096–1106. e1092.
  • Hoyo C, Murtha AP, Schildkraut JM, et al. Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST). BMC Public Health. 2011;11(1):46.
  • Liu Y, Murphy SK, Murtha AP, et al. Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics. 2012;7(7):735–746.
  • Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: united States. Adv Data. 2000(314):1–27.
  • Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2017;140(3). DOI:10.1542/peds.2017-1904
  • Bashir MR, Zhong X, Nickel MD, et al. Quantification of hepatic steatosis with a multistep adaptive fitting MRI approach: prospective validation against MR spectroscopy. AJR Am J Roentgenol. 2015;204(2):297–306.
  • Zhong X, Nickel MD, Kannengiesser SA, et al. Liver fat quantification using a multi-step adaptive fitting approach with multi-echo GRE imaging. Magn Reson Med. 2014;72(5):1353–1365.
  • Serai SD, Towbin AJ, Podberesky DJ. Pediatric liver MR elastography. Dig Dis Sci. 2012;57(10):2713–2719.
  • Goyal NP, Sawh MC, Ugalde-Nicalo P, et al. Evaluation of Quantitative Imaging Biomarkers for Early-phase Clinical Trials of Steatohepatitis in Adolescents. J Pediatr Gastroenterol Nutr. 2020;70(1):99–105.
  • Zeng J, Zhang X, Sun C, et al. Feasibility study and reference values of FibroScan 502 with M probe in healthy preschool children aged 5 years. BMC Pediatr. 2019;19(1):129.
  • Engelmann G, Gebhardt C, Wenning D, et al. Feasibility study and control values of transient elastography in healthy children. Eur J Pediatr. 2012;171(2):353–360.
  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357.
  • Geurtsen ML, Santos S, Felix JF, et al. Liver Fat and Cardiometabolic Risk Factors Among School-Age Children. Hepatology. 2020;72(1):119–129.
  • Di Martino M, Pacifico L, Bezzi M, et al. Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents. World J Gastroenterol. 2016;22(39):8812–8819.
  • Murphy SK, Huang Z, Hoyo C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS One. 2012;7(7):e40924.
  • Aryee MJ, Jaffe AE, Corrada-Bravo H, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363–1369.
  • R: a language and environment for statistcal computing. [ computer program]. 2019.
  • Roadmap Epigenomics C, Kundaje A, Meuleman W, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–330.
  • Peters TJ, Buckley MJ, Statham AL, et al. De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin. 2015;8(1):6.
  • Benjamini YH, Yosef. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Society of Statistical Society, Series B. 1995;57:289–300.
  • Vehmeijer FOL, Kupers LK, Sharp GC, et al. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies. Genome Med. 2020;12(1):105.
  • Urbina EM, Khoury PR, McCoy CE, et al. Triglyceride to HDL-C ratio and increased arterial stiffness in children, adolescents, and young adults. Pediatrics. 2013;131(4):e1082–1090.
  • Nur Zati Iwani AK, Jalaludin MY, Wan Mohd Zin RM, et al. TG : HDL-C Ratio Is a Good Marker to Identify Children Affected by Obesity with Increased Cardiometabolic Risk and Insulin Resistance. Int J Endocrinol. 2019;2019:8586167.
  • Young KA, Maturu A, Lorenzo C, et al. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance, β-cell function, and diabetes in Hispanics and African Americans. J Diabetes Complications. 2019;33(2):118–122.
  • Liu J, Fox CS, Hickson DA, et al. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J Clin Endocrinol Metab. 2010;95(12):5419–5426.
  • Maffeis C, Manfredi R, Trombetta M, et al. Insulin sensitivity is correlated with subcutaneous but not visceral body fat in overweight and obese prepubertal children. J Clin Endocrinol Metab. 2008;93(6):2122–2128.
  • Johansson Å, Eriksson N, Becker RC, et al. NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes: genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO). Circ Cardiovasc Genet. 2015;8(3):498–506.
  • Tatematsu M, Yoshida R, Morioka Y, et al. Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type–Specific Manner. J Immunol. 2016;196(9):3865–3876.
  • Ozer A, Tolun F, Aslan F, et al. The role of G protein-associated estrogen receptor (GPER) 1, corin, raftlin, and estrogen in etiopathogenesis of intrauterine growth retardation. J Matern Fetal Neonatal Med. 2021;34(5):755–760.
  • Spradley FT, Smith JA, Alexander BT, et al. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab. 2018;315(5):E795–E814.
  • Laqqan M, Tierling S, Alkhaled Y, et al. Spermatozoa from males with reduced fecundity exhibit differential DNA methylation patterns. Andrology. 2017;5(5):971–978.
  • Zaghlool SB, Sharma S, Molnar M, et al. Revealing the role of the human blood plasma proteome in obesity using genetic drivers. Nat Commun. 2021;12(1):1279.
  • Hu X, Wang R, Ren Z, et al. MiR-26b suppresses hepatocellular carcinoma development by negatively regulating ZNRD1 and Wnt/β-catenin signaling. Cancer Med. 2019;8(17):7359–7371.
  • Tabassum R, Ramo JT, Ripatti P, et al. Genetic architecture of human plasma lipidome and its link to cardiovascular disease. Nat Commun. 2019;10(1):4329.
  • Zeisel SC. Choline, Other Methyl-Donors and Epigenetics. Nutrients. 2017;9(5):445.
  • Wolff GL, Kodell RL, Moore SR, et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998;12(11):949–957.
  • Cordero P, Gomez-Uriz AM, Campion J, et al. Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet. Genes Nutr. 2013;8(1):105–113.
  • Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293–5300.
  • Waterland RA, Travisano M, Tahiliani KG, et al. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond). 2008;32(9):1373–1379.
  • Kim S, Yu N-K, Kaang B-K. CTCF as a multifunctional protein in genome regulation and gene expression. Exp Mol Med. 2015;47(6):e166.
  • Choi Y, Song M-J, Jung W-J, et al. Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ Signaling. Cell Mol Gastroenterol Hepatol. 2021;12(5):1761–1787.
  • Cai J, Li B, Zhu Y, et al. Prognostic Biomarker Identification Through Integrating the Gene Signatures of Hepatocellular Carcinoma Properties. EBioMedicine. 2017;19:18–30.
  • Wang Y, Zhang F, Wang J, et al. lncRNA LOC100132354 promotes angiogenesis through VEGFA/VEGFR2 signaling pathway in lung adenocarcinoma. Cancer Manag Res. 2018;10:4257–4266.
  • Tobi EW, Slieker RC, Luijk R, et al. DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. Sci Adv. 2018;4(1):eaao4364.
  • Choi SH, Ruggiero D, Sorice R, et al. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. PLoS Genet. 2016;12(2):e1005874.
  • Middleton MS, Van Natta ML, Heba ER, et al. Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease. Hepatology. 2018;67(3):858–872.
  • Schwimmer JB, Middleton MS, Behling C, et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology. 2015;61(6):1887–1895.
  • Gupta N, Jindal G, Nadda A, et al. Prevalence and risk factors for nonalcoholic fatty liver disease in obese children in rural Punjab, India. Journal of Family and Community Medicine. 2020;27(2):103–108.
  • Mohamed RZ, Jalaludin MY, Anuar Zaini A. Predictors of non-alcoholic fatty liver disease (NAFLD) among children with obesity. J Pediatr Endocrinol Metab. 2020;33(2):247–253.
  • Cohen CC, Perng W, Sundaram SS, et al. Hepatic Fat in Early Childhood Is Independently Associated With Estimated Insulin Resistance: the Healthy Start Study. J Clin Endocrinol Metab. 2021;106(11):3140–3150.

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