Integrated genetic and epigenetic analyses uncovered GLP1R association with metabolically healthy obesity.
Journal
International journal of obesity (2005)
ISSN: 1476-5497
Titre abrégé: Int J Obes (Lond)
Pays: England
ID NLM: 101256108
Informations de publication
Date de publication:
17 Nov 2023
17 Nov 2023
Historique:
received:
07
06
2023
accepted:
07
11
2023
revised:
24
10
2023
medline:
18
11
2023
pubmed:
18
11
2023
entrez:
18
11
2023
Statut:
aheadofprint
Résumé
Both genetic and epigenetic variations of GLP1R influence the development and progression of obesity. However, the underlying mechanism remains elusive. This study aims to explore the mediation roles of obesity-related methylation sites in GLP1R gene variants-obesity association. A total of 300 Chinese adult participants were included in this study and classified into two groups: 180 metabolically healthy obesity (MHO) cases and 120 metabolically healthy normal-weight (MHNW) controls. Questionnaire investigation, physical measurement and laboratory examination were assessed in all participants. 18 single nucleotide polymorphisms (SNPs) and 31 CpG sites were selected for genotype and methylation assays. Causal inference test (CIT) was performed to evaluate the associations between GLP1R genetic variation, DNA methylation and MHO. The study found that rs4714211 polymorphism of GLP1R gene was significantly associated with MHO. Additionally, methylation sites in the intronic region of GLP1R (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 12.13; GLP1R-68-CpG 17; GLP1R-68-CpG 21) were associated with MHO, and two of these methylation sites (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 17) partially mediated the association between genotypes and MHO. Not only the gene polymorphism, but also the DNA methylation of GLP1R was associated with MHO. Epigenetic changes in the methylome may in part explain the relationship between genetic variants and MHO.
Sections du résumé
BACKGROUND
BACKGROUND
Both genetic and epigenetic variations of GLP1R influence the development and progression of obesity. However, the underlying mechanism remains elusive. This study aims to explore the mediation roles of obesity-related methylation sites in GLP1R gene variants-obesity association.
METHODS
METHODS
A total of 300 Chinese adult participants were included in this study and classified into two groups: 180 metabolically healthy obesity (MHO) cases and 120 metabolically healthy normal-weight (MHNW) controls. Questionnaire investigation, physical measurement and laboratory examination were assessed in all participants. 18 single nucleotide polymorphisms (SNPs) and 31 CpG sites were selected for genotype and methylation assays. Causal inference test (CIT) was performed to evaluate the associations between GLP1R genetic variation, DNA methylation and MHO.
RESULTS
RESULTS
The study found that rs4714211 polymorphism of GLP1R gene was significantly associated with MHO. Additionally, methylation sites in the intronic region of GLP1R (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 12.13; GLP1R-68-CpG 17; GLP1R-68-CpG 21) were associated with MHO, and two of these methylation sites (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 17) partially mediated the association between genotypes and MHO.
CONCLUSIONS
CONCLUSIONS
Not only the gene polymorphism, but also the DNA methylation of GLP1R was associated with MHO. Epigenetic changes in the methylome may in part explain the relationship between genetic variants and MHO.
Identifiants
pubmed: 37978261
doi: 10.1038/s41366-023-01414-1
pii: 10.1038/s41366-023-01414-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–7.
pubmed: 17167477
doi: 10.1038/nature05488
Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Investig. 2017;127:1–4.
pubmed: 28045402
pmcid: 5199709
doi: 10.1172/JCI92035
Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1:152–62.
pubmed: 24622321
doi: 10.1016/S2213-8587(13)70062-7
Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med. 2013;159:758–69.
pubmed: 24297192
doi: 10.7326/0003-4819-159-11-201312030-00008
McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation. Endocr Rev. 2021;42:101–32.
pubmed: 33320179
doi: 10.1210/endrev/bnaa032
Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27:740–56.
pubmed: 29617641
doi: 10.1016/j.cmet.2018.03.001
Drucker DJ. GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab. 2022;57:101351.
pubmed: 34626851
doi: 10.1016/j.molmet.2021.101351
Grill HJ. A Role for GLP-1 in Treating Hyperphagia and Obesity. Endocrinology. 2020;161:1–14.
doi: 10.1210/endocr/bqaa093
Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab. 2021;46:101090.
pubmed: 32987188
doi: 10.1016/j.molmet.2020.101090
Li P, Tiwari HK, Lin WY, Allison DB, Chung WK, Leibel RL, et al. Genetic association analysis of 30 genes related to obesity in a European American population. Int J Obes. 2014;38:724–9.
doi: 10.1038/ijo.2013.140
de Luis DA, Ballesteros M, Lopez Guzman A, Ruiz E, Muñoz C, Penacho MA, et al. rs6923761 gene variant in glucagon-like peptide 1 receptor: Allelic frequencies and influence on cardiovascular risk factors in a multicenter study of Castilla-Leon. Clin Nutr. 2018;37:2144–8.
pubmed: 29128339
doi: 10.1016/j.clnu.2017.10.013
Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38:23–38.
pubmed: 22781841
doi: 10.1038/npp.2012.112
Heikkinen A, Bollepalli S, Ollikainen M. The potential of DNA methylation as a biomarker for obesity and smoking. J Intern Med. 2022;292:390–408.
pubmed: 35404524
pmcid: 9543926
doi: 10.1111/joim.13496
Ling C, Rönn T. Epigenetics in Human Obesity and Type 2 Diabetes. Cell Metab. 2019;29:1028–44.
pubmed: 30982733
pmcid: 6509280
doi: 10.1016/j.cmet.2019.03.009
Gao W, Liu JL, Lu X, Yang Q. Epigenetic regulation of energy metabolism in obesity. J Mol Cell Biol. 2021;13:480–99.
pubmed: 34289049
pmcid: 8530523
doi: 10.1093/jmcb/mjab043
Hall E, Dayeh T, Kirkpatrick CL, Wollheim CB, Dekker Nitert M, Ling C. DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC Med Genet. 2013;14:76.
pubmed: 23879380
pmcid: 3727960
doi: 10.1186/1471-2350-14-76
Kirchner H, Sinha I, Gao H, Ruby MA, Schönke M, Lindvall JM, et al. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol Metab. 2016;5:171–83.
pubmed: 26977391
pmcid: 4770265
doi: 10.1016/j.molmet.2015.12.004
Battram T, Richmond RC, Baglietto L, Haycock PC, Perduca V, Bojesen SE, et al. Appraising the causal relevance of DNA methylation for risk of lung cancer. Int J Epidemiol. 2019;48:1493–504.
pubmed: 31549173
pmcid: 6857764
doi: 10.1093/ije/dyz190
Sun M, Li S, Ning F, Zhang L, Wang W, Duan H, et al. Association between olfactory pathway gene variants and obesity in Chinese Han population: A case-control study based on genetic score. Gene. 2022;825:146442.
pubmed: 35337849
doi: 10.1016/j.gene.2022.146442
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–97.
Chen C, Lu FC. The guidelines for prevention and control of overweight and obesity in Chinese adults. Biomed Environ Sci. 2004;17:1–36.
pubmed: 15807475
Sun M, Jiang Y, Sun C, Li J, Guo X, Lv Y, et al. The associations between smoking and obesity in northeast China: a quantile regression analysis. Sci Rep. 2019;9:3732.
pubmed: 30872597
pmcid: 6418137
doi: 10.1038/s41598-019-39425-6
Yu ZB, Zhu Y, Li D, Wu MY, Tang ML, Wang JB, et al. Association between visit-to-visit variability of HbA(1c) and cognitive decline: a pooled analysis of two prospective population-based cohorts. Diabetologia. 2020;63:85–94.
pubmed: 31485707
doi: 10.1007/s00125-019-04986-8
Isgin-Atici K, Alsulami S, Turan-Demirci B, Surendran S, Sendur SN, Lay I, et al. FTO gene-lifestyle interactions on serum adiponectin concentrations and central obesity in a Turkish population. Int J Food Sci Nutr. 2021;72:375–85.
pubmed: 32746650
doi: 10.1080/09637486.2020.1802580
Du P, Zhang X, Huang CC, Jafari N, Kibbe WA, Hou L, et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinform. 2010;11:587.
doi: 10.1186/1471-2105-11-587
Yu H, Raut JR, Schöttker B, Holleczek B, Zhang Y, Brenner H. Individual and joint contributions of genetic and methylation risk scores for enhancing lung cancer risk stratification: data from a population-based cohort in Germany. Clin Epigenet. 2020;12:89.
doi: 10.1186/s13148-020-00872-y
Millstein J, Chen GK, Breton CV. cit: hypothesis testing software for mediation analysis in genomic applications. Bioinformatics. 2016;32:2364–5.
pubmed: 27153715
pmcid: 4965632
doi: 10.1093/bioinformatics/btw135
van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fischer K, Foco L, et al. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord. 2014;14:9.
pubmed: 24484869
pmcid: 3923238
doi: 10.1186/1472-6823-14-9
Lavie CJ, Laddu D, Arena R, Ortega FB, Alpert MA, Kushner RF. Healthy Weight and Obesity Prevention: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72:1506–31.
pubmed: 30236314
doi: 10.1016/j.jacc.2018.08.1037
Page LC, Freemark M. Role of GLP-1 Receptor Agonists in Pediatric Obesity: Benefits, Risks, and Approaches to Patient Selection. Curr Obes Rep. 2020;9:391–401.
pubmed: 33085056
doi: 10.1007/s13679-020-00409-7
Michałowska J, Miller-Kasprzak E, Seraszek-Jaros A, Mostowska A, Bogdański P. Association of GLP1R variants rs2268641 and rs6923761 with obesity and other metabolic parameters in a Polish cohort. Front Endocrinol. 2022;13:1000185.
doi: 10.3389/fendo.2022.1000185
Mansego ML, Milagro FI, Zulet M, Moreno-Aliaga MJ, Martínez JA. Differential DNA Methylation in Relation to Age and Health Risks of Obesity. Int J Mol Sci. 2015;16:16816–32.
pubmed: 26213922
pmcid: 4581172
doi: 10.3390/ijms160816816
Jönsson J, Renault KM, García-Calzón S, Perfilyev A, Estampador AC, Nørgaard K, et al. Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation, Which Associates With Body Composition in the Offspring. Diabetes. 2021;70:854–66.
pubmed: 33431374
pmcid: 7980200
doi: 10.2337/db20-0487
Willmer T, Goedecke JH, Dias S, Louw J, Pheiffer C. DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance. Clin Epigenet. 2020;12:141.
doi: 10.1186/s13148-020-00932-3
Schübeler D. Function and information content of DNA methylation. Nature. 2015;517:321–6.
pubmed: 25592537
doi: 10.1038/nature14192
Jurkowska RZ, Jurkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;12:206–22.
pubmed: 21243710
doi: 10.1002/cbic.201000195
Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13:484–92.
pubmed: 22641018
doi: 10.1038/nrg3230
Shayevitch R, Askayo D, Keydar I, Ast G. The importance of DNA methylation of exons on alternative splicing. RNA. 2018;24:1351–62.
pubmed: 30002084
pmcid: 6140467
doi: 10.1261/rna.064865.117
Li Y, Liu X, Tu R, Hou J, Zhuang G. Mendelian Randomization Analysis of the Association of SOCS3 Methylation with Abdominal Obesity. Nutrients. 2022;14:3824–34.
pubmed: 36145200
pmcid: 9503364
doi: 10.3390/nu14183824
Tu R, Liu X, Dong X, Li R, Liao W, Hou J, et al. Janus kinase 2 (JAK2) methylation and obesity: A Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2021;31:3484–91.
pubmed: 34656381
doi: 10.1016/j.numecd.2021.08.046
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.
pubmed: 29686387
pmcid: 6083837
doi: 10.1038/s41588-018-0099-7
Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017;318:1925–6.
pubmed: 29164242
doi: 10.1001/jama.2017.17219
Voisin S, Almén MS, Zheleznyakova GY, Lundberg L, Zarei S, Castillo S, et al. Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers. Genome Med. 2015;7:103.
pubmed: 26449484
pmcid: 4599317
doi: 10.1186/s13073-015-0225-4
Gutierrez-Arcelus M, Lappalainen T, Montgomery SB, Buil A, Ongen H, Yurovsky A, et al. Passive and active DNA methylation and the interplay with genetic variation in gene regulation. eLife. 2013;2:e00523.
pubmed: 23755361
pmcid: 3673336
doi: 10.7554/eLife.00523
Demerath EW, Guan W, Grove ML, Aslibekyan S, Mendelson M, Zhou YH, et al. Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet. 2015;24:4464–79.
pubmed: 25935004
pmcid: 4492394
doi: 10.1093/hmg/ddv161