Epigenome-wide Methylation Differences in a Group of Lean and Obese Women - A HUNT Study

Overview

Journal Sci Rep

Specialty Science

Date 2018 Nov 7

PMID 30397228

Citations 21

Authors

Kirsti Kvaloy

Christian Magnus Page

Turid Lingaas Holmen

Affiliations

Soon will be listed here.

Abstract

Knowledge of epigenetically regulated biomarkers linked to obesity development is still scarce. Improving molecular understanding of the involved factors and pathways would improve obesity phenotype characterization and reveal potentially relevant targets for obesity intervention. The Illumina Infinium HumanMethylation450 BeadChip was used in a leucocyte epigenome-wide association study (EWAS) to quantify differential DNA methylation in 60 lean compared with 60 obese young women. Replication was done in monozygotic twins discordant for obesity. At adolescence and adulthood, the two weight groups differed significantly in obesity-related traits and metabolic risk factors. Differential hypomethylation was overrepresented in obese compared to lean women. In the adjusted model, the EWAS revealed 10 differentially methylated CpG sites linked to 8 gene loci - COX6A1P2/FGD2, SBNO2, TEX41, RPS6KA2, IGHE/IGHG1/IGHD, DMAP1, SOCS3, and SETBP1- and an enhancer locus at chromosome 2 (2p25.1). The sites linked to TEX41, IGHE/IGHG1/IGHD, DMAP1, and SETBP1 were novel findings, while COX6A1P/FGD2, SBNO2, RPS6KA2, and SOCS3 had been identified previously with concordant direction of effects. RPS6KA2, DMAP1, and SETBP1 were replicated in the BMI-discordant monozygotic twin cohort using the FDR of 5%.

Citing Articles

Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.

Ling C, Vavakova M, Mir B, Sall J, Perfilyev A, Martin M BMC Med. 2024; 22(1):572.

PMID: 39623445 PMC: 11613913. DOI: 10.1186/s12916-024-03789-y.

Data Resource Profile: The HUNT Biobank.

Naess M, Kvaloy K, Sorgjerd E, Saetermo K, Noroy L, Rostad A Int J Epidemiol. 2024; 53(3).

PMID: 38836303 PMC: 11150882. DOI: 10.1093/ije/dyae073.

Epigenetics of the far northern Yakutian population.

Kalyakulina A, Yusipov I, Kondakova E, Bacalini M, Giuliani C, Sivtseva T Clin Epigenetics. 2023; 15(1):189.

PMID: 38053163 PMC: 10699032. DOI: 10.1186/s13148-023-01600-y.

A characteristic cerebellar biosignature for bipolar disorder, identified with fully automatic machine learning.

Thomaidis G, Papadimitriou K, Michos S, Chartampilas E, Tsamardinos I IBRO Neurosci Rep. 2023; 15:77-89.

PMID: 38025660 PMC: 10668096. DOI: 10.1016/j.ibneur.2023.06.008.

Genetics and Epigenetics in Obesity: What Do We Know so Far?.

Keller M, Svensson S, Rohde-Zimmermann K, Kovacs P, Bottcher Y Curr Obes Rep. 2023; 12(4):482-501.

PMID: 37819541 DOI: 10.1007/s13679-023-00526-z.

References

Lindstrom J, Tuomilehto J . The diabetes risk score: a practical tool to predict type 2 diabetes risk. Diabetes Care. 2003; 26(3):725-31. DOI: 10.2337/diacare.26.3.725. View

Kvaloy K, Kulle B, Romundstad P, Holmen T . Sex-specific effects of weight-affecting gene variants in a life course perspective--The HUNT Study, Norway. Int J Obes (Lond). 2013; 37(9):1221-9. DOI: 10.1038/ijo.2012.220. View

Mendelson M, Marioni R, Joehanes R, Liu C, Hedman A, Aslibekyan S . Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. PLoS Med. 2017; 14(1):e1002215. PMC: 5240936. DOI: 10.1371/journal.pmed.1002215. View

Jiao H, Arner P, Hoffstedt J, Brodin D, Dubern B, Czernichow S . Genome wide association study identifies KCNMA1 contributing to human obesity. BMC Med Genomics. 2011; 4:51. PMC: 3148553. DOI: 10.1186/1755-8794-4-51. View

Kadakia R, Zheng Y, Zhang Z, Zhang W, Hou L, Josefson J . Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation. Pediatr Obes. 2016; 12 Suppl 1:57-64. PMC: 5462869. DOI: 10.1111/ijpo.12204. View

Demerath E, Guan W, Grove M, Aslibekyan S, Mendelson M, Zhou Y . Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet. 2015; 24(15):4464-79. PMC: 4492394. DOI: 10.1093/hmg/ddv161. View

Almen M, Nilsson E, Jacobsson J, Kalnina I, Klovins J, Fredriksson R . Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity. Gene. 2014; 548(1):61-7. DOI: 10.1016/j.gene.2014.07.009. View

Pietilainen K, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keranen H . Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 2008; 5(3):e51. PMC: 2265758. DOI: 10.1371/journal.pmed.0050051. View

Ost A, Lempradl A, Casas E, Weigert M, Tiko T, Deniz M . Paternal diet defines offspring chromatin state and intergenerational obesity. Cell. 2014; 159(6):1352-64. DOI: 10.1016/j.cell.2014.11.005. View

10.

van Dijk S, Molloy P, Varinli H, Morrison J, Muhlhausler B . Epigenetics and human obesity. Int J Obes (Lond). 2014; 39(1):85-97. DOI: 10.1038/ijo.2014.34. View

11.

Balakrishnan A, Guruprasad K, Satyamoorthy K, Joshi M . Interleukin-6 determines protein stabilization of DNA methyltransferases and alters DNA promoter methylation of genes associated with insulin signaling and angiogenesis. Lab Invest. 2018; 98(9):1143-1158. DOI: 10.1038/s41374-018-0079-7. View

12.

Benton M, Johnstone A, Eccles D, Harmon B, Hayes M, Lea R . An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol. 2015; 16:8. PMC: 4301800. DOI: 10.1186/s13059-014-0569-x. View

13.

Scherag A, Jarick I, Grothe J, Biebermann H, Scherag S, Volckmar A . Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PLoS One. 2010; 5(11):e13967. PMC: 2981522. DOI: 10.1371/journal.pone.0013967. View

14.

Al Muftah W, Al-Shafai M, Zaghlool S, Visconti A, Tsai P, Kumar P . Epigenetic associations of type 2 diabetes and BMI in an Arab population. Clin Epigenetics. 2016; 8:13. PMC: 4730771. DOI: 10.1186/s13148-016-0177-6. View

15.

Must A, Spadano J, Coakley E, Field A, Colditz G, Dietz W . The disease burden associated with overweight and obesity. JAMA. 1999; 282(16):1523-9. DOI: 10.1001/jama.282.16.1523. View

16.

Roifman M, Choufani S, Turinsky A, Drewlo S, Keating S, Brudno M . Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction. Clin Epigenetics. 2016; 8:70. PMC: 4915063. DOI: 10.1186/s13148-016-0238-x. View

17.

Holmen T, Bratberg G, Krokstad S, Langhammer A, Hveem K, Midthjell K . Cohort profile of the Young-HUNT Study, Norway: a population-based study of adolescents. Int J Epidemiol. 2013; 43(2):536-44. DOI: 10.1093/ije/dys232. View

18.

Zeilinger S, Kuhnel B, Klopp N, Baurecht H, Kleinschmidt A, Gieger C . Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One. 2013; 8(5):e63812. PMC: 3656907. DOI: 10.1371/journal.pone.0063812. View

19.

Houseman E, Kile M, Christiani D, Ince T, Kelsey K, Marsit C . Reference-free deconvolution of DNA methylation data and mediation by cell composition effects. BMC Bioinformatics. 2016; 17:259. PMC: 4928286. DOI: 10.1186/s12859-016-1140-4. View

20.

Wahl S, Drong A, Lehne B, Loh M, Scott W, Kunze S . Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2016; 541(7635):81-86. PMC: 5570525. DOI: 10.1038/nature20784. View