Rs9939609 fto genotype associations with fto methylation level influences body mass and telomere length in an australian rural population

ABSTRACT BACKGROUND: The fat mass- and obesity-associated (FTO) gene influences energy homeostasis in humans. Although the obesity-related variant, rs9939609 has been replicated across a

number of cohort studies, there remains significant variance and a low to modest association. Telomere length is another commonly reported obesity risk factor. We hypothesize understanding

the associations between FTO rs9939609 with FTO methylation and telomere length will provide a more accurate assessment of obesity risk. METHODS: Overall, 942 participants free of diabetes

or pre-diabetes were included in the retrospective study. Leukocyte genomic DNA was analyzed for rs9939609 genotyping, FTO gene methylation and leukocyte telomere length (LTL) measurement.

RESULTS: In general linear models, rs9939609 AA genotypes were associated with increased fat percentage (3.15%, _P_=0.001), fat mass (4.16 kg, _P_=0.001), body mass index (BMI) (1.38,

_P_=0.006) and waist circumference (3.35 cm, _P_=0.006), but not with FTO methylation or LTL in this overall population. However, when participants were stratified into higher and lower FTO

methylation groups, the AA genotype possesses a 2.04-fold increased obesity risk in comparison to TT genotype (95%CI, 1.07-3.89, _P_=0.031) in participants with a higher FTO methylation

level, but this association was absent in the lower FTO methylation sub-group. Moreover, AT and AA genotype carriers were associated with shorter LTL compared to TT carriers (_P_=0.020 and

_P_=0.111, respectively) in the higher FTO methylation level group. However, this association was absent in the lower methylation group. Furthermore, FTO gene methylation level was

significantly associated with LTL in the 942 samples (_P_=0.017). CONCLUSIONS: FTO rs9939609 is associated with obesity risk and LTL in this study, where this association is only observed at

higher, but not lower, FTO methylation levels of participants. Our data suggest association of multiple factors, including FTO methylation level, may be involved in one of several

mechanisms underlying the commonly reported obesity risk of this FTO polymorphism. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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IN THE SINGAPORE CHINESE POPULATION Article Open access 03 May 2021 ASSOCIATION OF _ADIPOQ-_RS2241766 AND _FTO-_RS9939609 GENETIC VARIANTS WITH BODY MASS INDEX TRAJECTORY IN WOMEN OF

REPRODUCTIVE AGE OVER 6 YEARS OF FOLLOW-UP: THE PREDI STUDY Article 13 April 2021 ASSOCIATION BETWEEN THE _MTNR1B_, _HHEX_, _SLC30A8_, AND _TCF7L2_ SINGLE NUCLEOTIDE POLYMORPHISMS AND

CARDIOMETABOLIC RISK PROFILE IN A MIXED ANCESTRY SOUTH AFRICAN POPULATION Article Open access 10 October 2023 REFERENCES * Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P _et al_.

Variation in FTO contributes to childhood obesity and severe adult obesity. _Nat Genet_ 2007; 39: 724–726. Article  CAS  Google Scholar  * Frayling TM, Timpson NJ, Weedon MN, Zeggini E,

Freathy RM, Lindgren CM _et al_. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. _Science_ 2007; 316: 889–894. Article 

CAS  Google Scholar  * Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J _et al_. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related

traits. _PLoS Genet_ 2007; 3: e115. Article  Google Scholar  * Li H, Wu Y, Loos RJ, Hu FB, Liu Y, Wang J _et al_. Variants in the fat mass- and obesity-associated (FTO) gene are not

associated with obesity in a Chinese Han population. _Diabetes_ 2008; 57: 264–268. Article  CAS  Google Scholar  * Loos RJ, Bouchard C . FTO: the first gene contributing to common forms of

human obesity. _Obes Rev_ 2008; 9: 246–250. Article  CAS  Google Scholar  * den Hoed M, Westerterp-Plantenga MS, Bouwman FG, Mariman EC, Westerterp KR . Postprandial responses in hunger and

satiety are associated with the rs9939609 single nucleotide polymorphism in FTO. _Am J Clin Nutr_ 2009; 90: 1426–1432. Article  CAS  Google Scholar  * Olszewski PK, Fredriksson R, Olszewska

AM, Stephansson O, Alsio J, Radomska KJ _et al_. Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. _BMC Neurosci_ 2009; 10: 129. Article  Google Scholar

  * Qi Q, Downer MK, Kilpelainen TO, Taal HR, Barton SJ, Ntalla I _et al_. Dietary intake, FTO genetic variants, and adiposity: a combined analysis of over 16,000 children and adolescents.

_Diabetes_ 2015; 64: 2467–2476. Article  CAS  Google Scholar  * Labayen I, Ruiz JR, Ortega FB, Dallongeville J, Jimenez-Pavon D, Castillo MJ _et al_. Association between the FTO rs9939609

polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study. _Int J Obes_ 2011; 35: 66–71. Article  CAS  Google Scholar  * Gerken T, Girard

CA, Tung YC, Webby CJ, Saudek V, Hewitson KS _et al_. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. _Science_ 2007; 318: 1469–1472. Article 

CAS  Google Scholar  * Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z _et al_. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human

FTO. _FEBS Lett_ 2008; 582: 3313–3319. Article  CAS  Google Scholar  * Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y _et al_. N6-methyladenosine in nuclear RNA is a major substrate of the

obesity-associated FTO. _Nat Chem Biol_ 2011; 7: 885–887. Article  CAS  Google Scholar  * Mulligan CJ, D'Errico NC, Stees J, Hughes DA . Methylation changes at NR3C1 in newborns

associate with maternal prenatal stress exposure and newborn birth weight. _Epigenetics_ 2012; 7: 853–857. Article  CAS  Google Scholar  * Garcia-Lacarte M, Milagro FI, Zulet MA, Martinez

JA, Mansego ML . LINE-1 methylation levels, a biomarker of weight loss in obese subjects, are influenced by dietary antioxidant capacity. _Redox Rep_ 2016; 21: 67–74. Article  CAS  Google

Scholar  * Guenard F, Deshaies Y, Hould F, Lebel S, Tchernof A, Marceau P _et al_. Use of blood as a surrogate model for the assessment of visceral adipose tissue methylation progiles

associated with the metabolic syndrome in men. _J Mol Genet Med_ 2016; 10: 1. Article  Google Scholar  * Bacos K, Gillberg L, Volkov P, Olsson AH, Hansen T, Pedersen O _et al_. Blood-based

biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes. _Nat Commun_ 2016; 7: 11089. Article  CAS  Google Scholar  * Esterbauer H,

Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F _et al_. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.

_Nat Genet_ 2001; 28: 178–183. Article  CAS  Google Scholar  * Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K _et al_. Association of telomere length with type 2

diabetes, oxidative stress and UCP2 gene variation. _Atherosclerosis_ 2010; 209: 42–50. Article  CAS  Google Scholar  * Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B _et

al_. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. _Hum Mol Genet_ 2012; 21: 371–383. Article  CAS  Google Scholar  *

Zhao J, Goldberg J, Bremner JD, Vaccarino V . Global DNA methylation is associated with insulin resistance: a monozygotic twin study. _Diabetes_ 2012; 61: 542–546. Article  CAS  Google

Scholar  * Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y . DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. _J Autoimmun_ 2014; 50: 33–37.

Article  CAS  Google Scholar  * Houben JM, Moonen HJ, van Schooten FJ, Hageman GJ . Telomere length assessment: biomarker of chronic oxidative stress? _Free Radical Biol Med_ 2008; 44:

235–246. Article  CAS  Google Scholar  * Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C _et al_. Inflammation, oxidative

stress, and obesity. _Int J Mol Sci_ 2011; 12: 3117–3132. Article  CAS  Google Scholar  * An R, Yan H . Body weight status and telomere length in US middle-aged and older adults. _Obes Res

Clin Pract_ 2016; 11: 51–62. Article  Google Scholar  * Chen S, Yeh F, Lin J, Matsuguchi T, Blackburn E, Lee ET _et al_. Short leukocyte telomere length is associated with obesity in

American Indians: the Strong Heart Family study. _Aging_ 2014; 6: 380–389. Article  Google Scholar  * Njajou OT, Cawthon RM, Blackburn EH, Harris TB, Li R, Sanders JL _et al_. Shorter

telomeres are associated with obesity and weight gain in the elderly. _Int J Obes_ 2012; 36: 1176–1179. Article  CAS  Google Scholar  * Shin C, Kim NH, Baik I . Sex-specific association

between longitudinal changes in adiposity, FTO rs9939609 polymorphism, and leukocyte telomere length. _J Am Coll Nutr_ 2016; 35: 245–254. Article  CAS  Google Scholar  * Devers MC, Campbell

S, Shaw J, Zimmet P, Simmons D . Should liver function tests be included in definitions of metabolic syndrome? Evidence from the association between liver function tests, components of

metabolic syndrome and prevalent cardiovascular disease. _Diabet Med_ 2008; 25: 523–529. Article  CAS  Google Scholar  * American Diabetes Association. (2) Classification and diagnosis of

diabetes. _Diabetes Care_ 2015; 38 SUPPL: S8–S16. Article  Google Scholar  * [No authors listed]. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. _World

Health Organ Tech Rep Ser_ 2000; 894: 1–253. Google Scholar  * [No authors listed]. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in

adults—the evidence report. National Institutes of Health. _Obes Res_ 1998; 6 SUPPL 2: 51S–209S. Google Scholar  * Yu D, Simmons D . Association between lung capacity measurements and

abnormal glucose metabolism: findings from the Crossroads study. _Diabet Med_ 2014; 31: 595–599. Article  CAS  Google Scholar  * Cawthon RM . Telomere length measurement by a novel

monochrome multiplex quantitative PCR method. _Nucleic Acids Res_ 2009; 37: e21. Article  Google Scholar  * Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP _et al_. Association

of the FTO gene with BMI. _Obesity_ 2008; 16: 902–904. Article  CAS  Google Scholar  * Li H, Kilpelainen TO, Liu C, Zhu J, Liu Y, Hu C _et al_. Association of genetic variation in FTO with

risk of obesity and type 2 diabetes with data from 96,551 East and South Asians. _Diabetologia_ 2012; 55: 981–995. Article  CAS  Google Scholar  * Andreasen CH, Stender-Petersen KL, Mogensen

MS, Torekov SS, Wegner L, Andersen G _et al_. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. _Diabetes_ 2008; 57: 95–101. Article 

CAS  Google Scholar  * Cohen-Cline H, Lau R, Moudon AV, Turkheimer E, Duncan GE . Associations between fast-food consumption and body mass index: a cross-sectional study in adult twins.

_Twin Res Hum Genet_ 2015; 18: 375–382. Article  Google Scholar  * Loos RJ, Yeo GS . The bigger picture of FTO: the first GWAS-identified obesity gene. _Nat Rev Endocrinol_ 2014; 10: 51–61.

Article  CAS  Google Scholar  * Berulava T, Horsthemke B . The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels. _Eur J Hum Genet_ 2010; 18: 1054–1056.

Article  CAS  Google Scholar  * Jowett JB, Curran JE, Johnson MP, Carless MA, Goring HH, Dyer TD _et al_. Genetic variation at the FTO locus influences RBL2 gene expression. _Diabetes_ 2010;

59: 726–732. Article  CAS  Google Scholar  * Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C _et al_. FTO obesity variant circuitry and adipocyte browning in humans. _N Engl

J Med_ 2015; 373: 895–907. Article  CAS  Google Scholar  * Almen MS, Jacobsson JA, Moschonis G, Benedict C, Chrousos GP, Fredriksson R _et al_. Genome wide analysis reveals association of a

FTO gene variant with epigenetic changes. _Genomics_ 2012; 99: 132–137. Article  CAS  Google Scholar  * Tan M, Wei C, Price CM . The telomeric protein Rap1 is conserved in vertebrates and

is expressed from a bidirectional promoter positioned between the Rap1 and KARS genes. _Gene_ 2003; 323: 1–10. Article  CAS  Google Scholar  * Johnston SD, Enomoto S, Schneper L, McClellan

MC, Twu F, Montgomery ND _et al_. CAC3(MSI1) suppression of RAS2(G19V) is independent of chromatin assembly factor I and mediated by NPR1. _Mol Cell Biol_ 2001; 21: 1784–1794. Article  CAS 

Google Scholar  * Grandin N, Reed SI, Charbonneau M . Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13. _Genes Dev_ 1997; 11:

512–527. Article  CAS  Google Scholar  * Grandin N, Damon C, Charbonneau M . Ten1 functions in telomere end protection and length regulation in association with Stn1 and Cdc13. _EMBO J_

2001; 20: 1173–1183. Article  CAS  Google Scholar  * Bai B, Liang Y, Xu C, Lee MY, Xu A, Wu D _et al_. Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the

development of endothelial senescence and atherosclerosis. _Circulation_ 2012; 126: 729–740. Article  CAS  Google Scholar  * Minegishi Y, Haramizu S, Misawa K, Shimotoyodome A, Hase T,

Murase T . Deletion of nuclear factor-kappaB p50 upregulates fatty acid utilization and contributes to an anti-obesity and high-endurance phenotype in mice. _Am J Physiol Endocrinol Metab_

2015; 309: E523–E533. Article  CAS  Google Scholar  * Schubeler D . Function and information content of DNA methylation. _Nature_ 2015; 517: 321–326. Article  CAS  Google Scholar  * Lay FD,

Liu Y, Kelly TK, Witt H, Farnham PJ, Jones PA _et al_. The role of DNA methylation in directing the functional organization of the cancer epigenome. _Genome Res_ 2015; 25: 467–477. Article 

CAS  Google Scholar  * Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L _et al_. Overexpression of Fto leads to increased food intake and results in obesity. _Nat Genet_ 2010; 42:

1086–1092. Article  CAS  Google Scholar  * Mundstock E, Sarria EE, Zatti H, Mattos Louzada F, Kich Grun L, Herbert Jones M _et al_. Effect of obesity on telomere length: Systematic review

and meta-analysis. _Obesity_ 2015; 23: 2165–2174. Article  Google Scholar  * Zhao J, Zhu Y, Lin J, Matsuguchi T, Blackburn E, Zhang Y _et al_. Short leukocyte telomere length predicts risk

of diabetes in American Indians: the strong heart family study. _Diabetes_ 2014; 63: 354–362. Article  CAS  Google Scholar  * Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, Herbert

A _et al_. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. _Aging cell_ 2006; 5: 325–330. Article  CAS  Google

Scholar  * Verhulst S, Dalgard C, Labat C, Kark JD, Kimura M, Christensen K _et al_. A short leucocyte telomere length is associated with development of insulin resistance. _Diabetologia_

2016; 59: 1258–1265. Article  CAS  Google Scholar  * Toperoff G, Kark JD, Aran D, Nassar H, Ahmad WA, Sinnreich R _et al_. Premature aging of leukocyte DNA methylation is associated with

type 2 diabetes prevalence. _Clin Epigenet_ 2015; 7: 35. Article  Google Scholar  * Sun Q, Shi L, Prescott J, Chiuve SE, Hu FB, De Vivo I _et al_. Healthy lifestyle and leukocyte telomere

length in U.S. women. _PLoS One_ 2012; 7: e38374. Article  CAS  Google Scholar  * Bekaert S, De Meyer T, Rietzschel ER, De Buyzere ML, De Bacquer D, Langlois M _et al_. Telomere length and

cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. _Aging Cell_ 2007; 6: 639–647. Article  CAS  Google Scholar  Download references AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Rural Clinical School, University of New South Wales,, Sydney, New South Wales, Australia Y Zhou & C S McLachlan * Rural Clinical School,

University of MelbourneI, Shepparton, Victoria, Australia D Simmons * School of Medicine, Western Sydney University, Sydney, New South Wales, Australia D Simmons * School of Medical Sciences

and Bosch Institute, D Lai * University of Sydney, Sydney, New South Wales, Australia D Lai * Discipline of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales,

Australia B D Hambly Authors * Y Zhou View author publications You can also search for this author inPubMed Google Scholar * D Simmons View author publications You can also search for this

author inPubMed Google Scholar * D Lai View author publications You can also search for this author inPubMed Google Scholar * B D Hambly View author publications You can also search for this

author inPubMed Google Scholar * C S McLachlan View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to C S McLachlan.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zhou, Y., Simmons,

D., Lai, D. _et al._ rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population. _Int J Obes_ 41, 1427–1433

(2017). https://doi.org/10.1038/ijo.2017.127 Download citation * Received: 14 November 2016 * Revised: 26 March 2017 * Accepted: 07 May 2017 * Published: 31 May 2017 * Issue Date: September

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