Skip to main content
SpringerLink
Log in

The FTO Gene and Diseases: The Role of Genetic Polymorphism, Epigenetic Modifications, and Environmental Factors

  • REVIEWS AND THEORETICAL ARTICLES
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

The review provides information on the function of the FTO gene (known as the fat mass and obesity-associated gene) and the encoded enzyme, on the functional role of single nucleotide polymorphisms (SNPs) in coding and noncoding gene regions and the range of their competences, and on association of the FTO polymorphisms with diseases and traits. Factors that have modifying effect on the contribution of polymorphisms to the risk of disease development and trait variability are discussed. The FTO gene encodes alpha-ketoglutarate-dependent dioxygenase, which has a wide range of competences (including demethylation of RNA and single-stranded DNA), which are important for the functioning of the body. Nonsynonymous substitutions in the FTO gene lead to the development of orphan autosomal recessive disease (OMIM 612938). In the FTO noncoding regions, a wide range of variants has been detected, including those of regulatory importance (eQTL, sQTL, etc.). The competence of these variants extends to both FTO and neighboring genes (IRX3, IRX5, RPGRIP1L). Intronic polymorphisms of the FTO gene have been found to be associated with a wide range of multifactorial diseases and traits (obesity and related anthropometric traits, lipid metabolism markers, diabetes mellitus (type 2), coronary heart disease, metabolic syndrome, and other diseases). In the overwhelming majority of studies, the same allele variants are classified as risk ones; however, previously established associations of the FTO polymorphisms with diseases (traits) are demonstrated not in all populations. It is demonstrated that the effects of the FTO gene SNPs can be modified by exogenous and endogenous environmental factors, as well as lifestyle (including the type of diet, consumption of certain nutrients and medications, physical activity, etc.). Epigenetic factors (DNA methylation at CpG sites) are also important for regulating the level of FTO expression and the effects of individual SNPs. The accumulated data on the FTO structure and function, as well as the functional role of the encoded enzyme, make this gene attractive from the point of view of developing personalized approaches to healthcare.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Peters, T., Ausmeier, K., and Rüther, U., Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation, Mamm. Genome, 1999, vol. 10, pp. 983—986.

    Article  CAS  PubMed  Google Scholar 

  2. Online Mendelian Inheritance in Man. http://www.omim.org/. Accessed October, 2019.

  3. The NHGRI-EBI Catalog of published genome-wide association studies. https://www.ebi.ac.uk/gwas/. Accessed October, 2019.

  4. The UniProt Consortium, UniProt: the universal protein knowledgebase, Nucleic Acids Res., 2017, vol. 45, pp. D158—D169. http://www.uniprot.org/. Accessed October, 2019.

  5. Jia, G., Yang, C.G., Yang, S., et al., Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO, FEBS Lett., 2008, vol. 582, nos. 23—24, pp. 3313—3319. https://doi.org/10.1016/j.febslet.2008.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Berulava, T., Rahmann, S., Rademacher, K., et al., N6-adenosine methylation in miRNAs, PLoS One, 2015, vol. 10, no. 2. e0118438. https://doi.org/10.1371/journal.pone.0118438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mauer, J., Luo, X., Blanjoie, A., et al., Reversible methylation of m6Am in the 5' cap controls mRNA stability, Nature, 2017, vol. 541, no. 7637, pp. 371—375. https://doi.org/10.1038/nature21022

    Article  CAS  PubMed  Google Scholar 

  8. GTExPortal. https://gtexportal.org/. Accessed October, 2019.

  9. Berulava, T. and Horsthemke, B., The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels, Eur. J. Hum. Genet., 2010, vol. 18, no. 9, pp. 1054—1056. https://doi.org/10.1038/ejhg.2010.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stratigopoulos, G., LeDuc, C.A., Cremona, M.L., et al., Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling, J. Biol. Chem., 2011, vol. 286, no. 3, pp. 2155—2170. https://doi.org/10.1074/jbc.M110.188482

    Article  CAS  PubMed  Google Scholar 

  11. Karra, E., O’Daly, O.G., Choudhury, A.I., et al., A link between FTO, ghrelin, and impaired brain food-cue responsivity, J. Clin. Invest., 2013, vol. 123, no. 8, pp. 3539—3551. https://doi.org/10.1172/JCI44403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Peters, U., North, K.E., Sethupathy, P., et al., A systematic mapping approach of 16q12.2/FTO and BMI in more than 20 000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study, PLoS Genet., 2013, vol. 9, no. 1. e1003171. https://doi.org/10.1371/journal.pgen.1003171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Claussnitzer, M., Dankel, S.N., Kim, K.-H., et al., FTO obesity variant circuitry and adipocyte browning in humans, New Eng. J. Med., 2015, vol. 373, pp. 895—907. https://doi.org/10.1056/NEJMc1513316

    Article  CAS  PubMed  Google Scholar 

  14. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/. Accessed October, 2019.

  15. Ensembl genome browser 88. http://www.ensembl. org/. Accessed October, 2019.

  16. VISTA Enhancer Browser. https://enhancer.lbl.gov/. Accessed October, 2019.

  17. Gene Ontology and GO Annotations. https://www. ebi.ac.uk/QuickGO/. Accessed October, 2019.

  18. Expression Atlas. https://www.ebi.ac.uk/gxa/genes/. Accessed October, 2019.

  19. Boissel, S., Reish, O., Proulx, K., et al., Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations, Am. J. Hum. Genet., 2009, vol. 85, no. 1, pp. 106—111. https://doi.org/10.1016/j.ajhg.2009.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. The portal for rare diseases and orphan drugs. https://www.orpha.net/. Accessed October, 2019.

  21. GIANT: Genetic Investigation of Anthropometric Traits. http://portals.broadinstitute.org/collaboration/giant/. Accessed October, 2019.

  22. Mao, L., Fang, Y., Campbell, M., and Southerland, W.M., Population differentiation in allele frequencies of obesity-associated SNPs, BMC Genomics, 2017, vol. 18, no. 1, p. 861. https://doi.org/10.1186/s12864-017-4262-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, W., Liu, Q., Deng, X., et al., Association between obesity and puberty timing: a systematic review and meta-analysis, Int. J. Environ. Res., Public Health, 2017, vol. 14, no. 10. pii: E1266. https://doi.org/10.3390/ijerph14101266

    Article  Google Scholar 

  24. Zav’yalova, L.G., Denisova, D.V., Simonova, G.I., et al., Association of polymorphisms of genes FTO and TCF7L2 with cardiometabolic parameters of the adolescents in Siberia, Byull. Sib. Otd. Ross. Akad. Med. Nauk, 2011, vol. 31, no. 5, pp. 5—13.

    Google Scholar 

  25. Kochetova, O.V., Korytina, G.F., Akhmadishina, L.Z., et al., Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population, Russ. J. Genet., 2014, vol. 50, no. 12, pp. 1326—1333. https://doi.org/10.1134/S1022795414120059

    Article  CAS  Google Scholar 

  26. Nikitin, A.G., Potapov, V.A., Brovkin, A.N., et al., Association of FTO, KCNJ11, SLC30A8, and CDKN2B polymorphisms with type 2 diabetes mellitus, Mol. Biol. (Moscow), 2015, vol. 49, no. 1, pp. 103—111. https://doi.org/10.1134/S0026893315010112

    Article  CAS  Google Scholar 

  27. Huang, X., Zhao, J., Yang, M., et al., Association between FTO gene polymorphism (rs9939609 T/A) and cancer risk: a meta-analysis, Eur. J. Cancer Care (Engl.), 2017, vol. 26, no. 5. https://doi.org/10.1111/ecc.12464

  28. Al-Serri, A., Al-Bustan, S.A., Kamkar, M., et al., Association of FTO rs9939609 with obesity in the Kuwaiti population: a Public Health Concern?, Med. Princ. Pract., 2018, vol. 27, no. 2, pp. 145—151. https://doi.org/10.1159/000486767

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sabarneh, A., Ereqat, S., Cauchi, S., et al., Common FTO rs9939609 variant and risk of type 2 diabetes in Palestine, BMC Med. Genet., 2018, vol. 19, no. 1, p. 156. https://doi.org/10.1186/s12881-018-0668-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang, Q., Xia, X., Fang, S., and Yuan, X., Relationship between fat mass and obesity-associated (FTO) gene polymorphisms with obesity and metabolic syndrome in ethnic Mongolians, Med. Sci. Monit., 2018, vol. 24, pp. 8232—8238. https://doi.org/10.12659/MSM.910928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mozafarizadeh, M., Mohammadi, M., Sadeghi, S., et al., Evaluation of FTO rs9939609 and MC4R rs17782313 polymorphisms as prognostic biomarkers of obesity: a population-based cross-sectional study, Oman Med. J., 2019, vol. 34, no. 1, pp. 56—62. https://doi.org/10.5001/omj.2019.09

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fisher, E., Schulze, M.B., Stefan, N., et al., Association of the FTO rs9939609 single nucleotide polymorphism with C-reactive protein levels, Obesity (Silver Spring), 2009, vol. 17, no. 2, pp. 330—334. https://doi.org/10.1038/oby.2008.465

    Article  CAS  PubMed  Google Scholar 

  33. Tupikowska-Marzec, M., Kolačkov, K., Zdrojowy-Wełna, A., et al., The influence of FTO polymorphism rs9939609 on obesity, some clinical features, and disturbance of carbohydrate metabolism in patients with psoriasis, Biomed. Res. Int., 2019, article 7304345. https://doi.org/10.1155/2019/7304345

  34. Naderi, M., Hashemi, M., Dejkam, N., et al., Association study of the FTO gene polymorphisms with the risk of pulmonary tuberculosis in a sample of Iranian population, Acta Microbiol. Immunol. Hung., 2017, vol. 64, no. 1, pp. 91—99. https://doi.org/10.1556/030.64.2017.010

    Article  CAS  PubMed  Google Scholar 

  35. Liu, A.L., Liao, H.Q., Zhou, J., et al., The role of FTO variants in the susceptibility of polycystic ovary syndrome and in vitro fertilization outcomes in Chinese women, Gynecol. Endocrinol., 2018, vol. 34, no. 8, pp. 719—723. https://doi.org/10.1080/09513590.2018.1441397

    Article  CAS  PubMed  Google Scholar 

  36. Saucedo, R., Valencia, J., Gutierrez, C., et al., Gene variants in the FTO gene are associated with adiponectin and TNF-alpha levels in gestational diabetes mellitus, Diabetol. Metab. Syndr., 2017, vol. 9, no. 32. https://doi.org/10.1186/s13098-017-0234-0

  37. Wu, Z., Yang, Y., and Qiu, G., Association study between the polymorphisms of the fat mass- and obesity-associated gene with the risk of intervertebral disc degeneration in the Han Chinese population, Genet. Test. Mol. Biomarkers, 2013, vol. 17, no. 10, pp. 756—762. https://doi.org/10.1089/gtmb.2013.0225

    Article  CAS  PubMed  Google Scholar 

  38. Chen, J., Zhu, Q., Liu, G., et al., Fat mass and obesity-associated (FTO) gene polymorphisms are associated with risk of intervertebral disc degeneration in Chinese Han population: a case control study, Med. Sci. Monit., 2018, vol. 24, pp. 5598—5609. https://doi.org/10.12659/MSM.911101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. González-Herrera, L., Zavala-Castro, J., Ayala-Cáceres, C., et al., Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school-aged children with obesity/overweight and with normal weight, Am. J. Hum. Biol., 2019, vol. 31, no. 1. e23192. https://doi.org/10.1002/ajhb.23192

    Article  PubMed  Google Scholar 

  40. Chen, B., Li, Z., Chen, J., et al., Association of fat mass and obesity-associated and retinitis pigmentosa guanosine triphosphatase (GTPase) regulator-interacting protein-1 like polymorphisms with body mass index in Chinese women, Endocr. J., 2018, vol. 65, no. 7, pp. 783—791. https://doi.org/10.1507/endocrj.EJ17-0554

    Article  CAS  PubMed  Google Scholar 

  41. Shahid, S.U., Shabana, Cooper, J.A., et al., Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants, Atherosclerosis, 2017, vol. 258, pp. 1—7. https://doi.org/10.1016/j.atherosclerosis.2017.01.024

    Article  CAS  PubMed  Google Scholar 

  42. Saber-Ayad, M., Manzoor, S., El Serafi, A., et al., The FTO rs9939609 “A” allele is associated with impaired fasting glucose and insulin resistance in Emirati population, Gene, 2019, vol. 681, pp. 93—98. https://doi.org/10.1016/j.gene.2018.09.053

    Article  CAS  PubMed  Google Scholar 

  43. Mitropoulos, K., Merkouri Papadima, E., Xiromerisiou, G., et al., Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients, Hum. Genomics, 2017, vol. 11, no. 1, p. 30. https://doi.org/10.1186/s40246-017-0126-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kilpeläinen, T.O., Zillikens, M.C., Stančákova, A., et al., Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile, Nat. Genet., 2011, vol. 43, no. 8, pp. 753—760. https://doi.org/10.1038/ng.866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ningombam, S.S., Chhungi, V., Newmei, M.K., et al., Differential distribution and association of FTO rs9939609 gene polymorphism with obesity: a cross-sectional study among two tribal populations of India with East-Asian ancestry, Gene, 2018, vol. 647, pp. 198—204. https://doi.org/10.1016/j.gene.2018.01.009

    Article  CAS  PubMed  Google Scholar 

  46. Saldaña-Alvarez, Y., Salas-Martínez, M.G., García-Ortiz, H., et al., Gender-dependent association of FTO polymorphisms with body mass index in Mexicans, PLoS One, 2016, vol. 11, no. 1. e0145984. https://doi.org/10.1371/journal.pone.0145984

    Article  PubMed  PubMed Central  Google Scholar 

  47. Oyeyemi, B.F., Ologunde, C.A., Olaoye, A.B., and Alamukii, N.A., FTO gene associates and interacts with obesity risk, physical activity, energy intake, and time spent sitting: pilot study in a Nigerian population, J. Obes., 2017, article 3245270. https://doi.org/10.1155/2017/3245270

  48. Rask-Andersen, M., Karlsson, T., Ek, W.E., and Johansson, Å., Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status, PLoS Genet., 2017, vol. 13, no. 9. e1006977. https://doi.org/10.1371/journal.pgen.1006977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Abadi, A., Alyass, A., Robiou du Pont, S., et al., Penetrance of polygenic obesity susceptibility loci across the body mass index distribution, Am. J. Hum. Genet., 2017, vol. 101, no. 6, pp. 925—938. https://doi.org/10.1016/j.ajhg.2017.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun, X., Luquet, S., and Small, D.M., DRD2: bridging the genome and ingestive behavior, Trends Cogn. Sci., 2017, vol. 21, no. 5, pp. 372—384. https://doi.org/10.1016/j.tics.2017.03.004

    Article  PubMed  PubMed Central  Google Scholar 

  51. Nagpal, S., Gibson, G., and Marigorta, U.M., Pervasive modulation of obesity risk by the environment and genomic background, Genes (Basel), 2018, vol. 9, no. 8. pii: E411. https://doi.org/10.3390/genes9080411

    Article  CAS  PubMed  Google Scholar 

  52. Kalantari, N., Keshavarz Mohammadi, N., Izadi, P., et al., A haplotype of three SNPs in FTO had a strong association with body composition and BMI in Iranian male adolescents, PLoS One, 2018, vol. 13, no. 4. e0195589. https://doi.org/10.1371/journal.pone.0195589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, X., Huang, N., Yang, M., et al., FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis, Cell Death Dis., 2017, vol. 8, no. 3. e2702. https://doi.org/10.1038/cddis.2017.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Church, C., Moir, L., McMurray, F., et al., Overexpression of Fto leads to increased food intake and results in obesity, Nat. Genet., 2010, vol. 42, no. 12, pp. 1086—1092. https://doi.org/10.1038/ng.713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gerken, T., Girard, C.A., Tung, Y.C., et al., The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase, Science, 2007, vol. 318, no. 5855, pp. 1469—1472. https://doi.org/10.1126/science.1151710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. den Hoed, M., Westerterp-Plantenga, M.S., Bouwman, F.G., et al., Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO,Am. J. Clin. Nutr., 2009, vol. 90, no. 5, pp. 1426—1432. https://doi.org/10.3945/ajcn.2009.28053

    Article  CAS  PubMed  Google Scholar 

  57. Magno, F.C.C.M., Guaraná, H.C., Fonseca, A.C.P., et al., Influence of FTO rs9939609 polymorphism on appetite, ghrelin, leptin, IL6, TNFα levels, and food intake of women with morbid obesity, Diabetes Metab. Syndr. Obes., 2018, vol. 11, pp. 199—207. https://doi.org/10.2147/DMSO.S154978

    Article  PubMed  PubMed Central  Google Scholar 

  58. Skuladottir, G.V., Oskarsdottir, H., Pisanu, C., et al., Plasma stearoyl-CoA desaturase activity indices and bile acid concentrations after a low-fat meal: association with a genetic variant in the FTO gene, Diabetes Metab. Syndr. Obes., 2018, vol. 11, pp. 611—618. https://doi.org/10.2147/DMSO.S175730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao, X., Yang, Y., Sun, B.F., et al., FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis, Cell Res., 2014, vol. 24, no. 12, pp. 1403—1419. https://doi.org/10.1038/cr.2014.151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, X., Zhu, L., Chen, J., and Wang, Y., mRNA m6A methylation downregulates adipogenesis in porcine adipocytes, Biochem. Biophys. Res. Commun., 2015, vol. 459, no. 2, pp. 201—207. https://doi.org/10.1016/j.bbrc.2015.02.048

    Article  CAS  PubMed  Google Scholar 

  61. Martin Carli, J.F., LeDuc, C.A., Zhang, Y., et al., FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications, J. Lipid Res., 2018, vol. 59, no. 8, pp. 1446—1460. https://doi.org/10.1194/jlr.M085555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Merkestein, M., McTaggart, J.S., Lee, S., et al., Changes in gene expression associated with FTO overexpression in mice, PLoS One, 2014, vol. 9, no. 5. e97162. https://doi.org/10.1371/journal.pone.0097162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhuang, C., Zhuang, C., Luo, X., et al., N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis, J. Cell Mol. Med., 2019, vol. 23, no. 3, pp. 2163—2173. https://doi.org/10.1111/jcmm.14128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xu, D., Shao, W., Jiang, Y., et al., FTO expression is associated with the occurrence of gastric cancer and prognosis, Oncol. Rep., 2017, vol. 38, no. 4, pp. 2285—2292. https://doi.org/10.3892/or.2017.5904

    Article  CAS  PubMed  Google Scholar 

  65. Liu, Y., Wang, R., Zhang, L., et al., The lipid metabolism gene FTO influences breast cancer cell energy metabolism via the PI3K/AKT signaling pathway, Oncol. Lett., 2017, vol. 13, no. 6, pp. 4685—4690. https://doi.org/10.3892/ol.2017.6038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu, J., Ren, D., Du, Z., et al., m6A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression, Biochem. Biophys. Res. Commun., 2018, vol. 502, no. 4, pp. 456—464. https://doi.org/10.1016/j.bbrc.2018.05.175

    Article  CAS  PubMed  Google Scholar 

  67. Cui, Q., Shi, H., Ye, P., et al., m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells, Cell Rep., 2017, vol. 18, no. 11, pp. 2622—2634. https://doi.org/10.1016/j.celrep.2017.02.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Huđek, A., Škara, L., Smolkovič, B., et al., Higher prevalence of FTO gene risk genotypes AA rs9939609, CC rs1421085, and GG rs17817449 and saliva containing Staphylococcus aureus in obese women in Croatia, Nutr. Res., 2017, vol. 50, pp. 94—103. https://doi.org/10.1016/j.nutres.2017.12.005

    Article  CAS  PubMed  Google Scholar 

  69. IntAct Molecular Interaction. https://www.ebi.ac.uk/ intact/. Accessed October, 2019.

  70. Orchard, S., Ammari, M., Aranda, B., et al., The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases, Nucleic Acids Res., 2014, vol. 42, pp. D358—D363. https://doi.org/10.1093/nar/gkt1115

    Article  CAS  PubMed  Google Scholar 

  71. Song, T., Yang, Y., Wei, H., et al., Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation, Nucleic Acids Res., 2019. pii: gkz312. https://doi.org/10.1093/nar/gkz312

  72. Wu, W., Feng, J., Jiang, D., et al., AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine, Sci. Rep., 2017, vol. 7, article 41606. https://doi.org/10.1038/srep41606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tan, N.N., Tang, H.L., Lin, G.W., et al., Epigenetic downregulation of Scn3a expression by valproate: a possible role in its anticonvulsant activity, Mol. Neurobiol., 2017, vol. 54, no. 4, pp. 2831—2842. https://doi.org/10.1007/s12035-016-9871-9

    Article  CAS  PubMed  Google Scholar 

  74. Heng, J., Tian, M., Zhang, W., et al., Maternal heat stress regulates the early fat deposition partly through modification of m6A RNA methylation in neonatal piglets, Cell Stress Chaperones, 2019, vol. 24, no. 3, pp. 635—645. https://doi.org/10.1007/s12192-019-01002-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang, Y., Guo, F., and Zhao, R., Hepatic expression of FTO and fatty acid metabolic genes changes in response to lipopolysaccharide with alterations in m6A modification of relevant mRNAs in the chicken, Br. Poult. Sci., 2016, vol. 57, no. 5, pp. 628—635. https://doi.org/10.1080/00071668.2016.1201199

    Article  CAS  PubMed  Google Scholar 

  76. Lu, N., Li, X., Yu, J., et al., Curcumin attenuates lipopolysaccharide-induced hepatic lipid metabolism disorder by modification of m6A RNA methylation in piglets, Lipids, 2018, vol. 53, no. 1, pp. 53—63. https://doi.org/10.1002/lipd.12023

    Article  CAS  PubMed  Google Scholar 

  77. Vujovic, P., Stamenkovic, S., Jasnic, N., et al., Fasting induced cytoplasmic Fto expression in some neurons of rat hypothalamus, PLoS One, 2013, vol. 8, no. 5. e63694. https://doi.org/10.1371/journal.pone.0063694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nowacka-Woszuk, J., Pruszynska-Oszmalek, E., Szydlowski, M., and Szczerbal, I., Nutrition modulates Fto and Irx3 gene transcript levels, but does not alter their DNA methylation profiles in rat white adipose tissues, Gene, 2017, vol. 610, pp. 44—48. https://doi.org/10.1016/j.gene.2017.02.002

    Article  CAS  PubMed  Google Scholar 

  79. Chen, J., Zhou, X., Wu, W., et al., FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice, J. Physiol. Biochem., 2015, vol. 71, no. 3, pp. 405—413. https://doi.org/10.1007/s13105-015-0420-1

    Article  CAS  PubMed  Google Scholar 

  80. Li, X., Yang, J., Zhu, Y., et al., Mouse maternal high-fat intake dynamically programmed mRNA m6A modifications in adipose and skeletal muscle tissues in offspring, Int. J. Mol. Sci., 2016, vol. 17, no. 8. pii: E1336. https://doi.org/10.3390/ijms17081336

    Article  CAS  PubMed  Google Scholar 

  81. Melnik, B.C., Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases, J. Transl. Med., 2015, vol. 13, no. 385. https://doi.org/10.1186/s12967-015-0746-z

  82. Melnik, B.C. and Schmitz, G., Milk’s role as an epigenetic regulator in health and disease, Diseases, 2017, vol. 5, no. 1. pii: E12. https://doi.org/10.3390/diseases5010012

    Article  CAS  PubMed  Google Scholar 

  83. Mizuno, T.M., Lew, P.S., Luo, Y., and Leckstrom, A., Negative regulation of hepatic fat mass and obesity associated (Fto) gene expression by insulin, Life Sci., 2017, vol. 170, pp. 50—55. https://doi.org/10.1016/j.lfs.2016.11.027

    Article  CAS  PubMed  Google Scholar 

  84. Lai, A.G., Forde, D., Chang, W.H., et al., Glucose and glutamine availability regulate HepG2 transcriptional responses to low oxygen, Wellcome Open Res., 2018, vol. 3, no. 126. https://doi.org/10.12688/wellcomeopenres.14839.1

  85. Wu, R., Yao, Y., Jiang, Q., et al., Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner, Int. J. Obes. (London), 2018, vol. 42, no. 7, pp. 1378—1388. https://doi.org/10.1038/s41366-018-0082-5

    Article  CAS  Google Scholar 

  86. Yadav, D.K., Shrestha, S., Lillycrop, K.A., et al., Vitamin B12 supplementation influences methylation of genes associated with type 2 diabetes and its intermediate traits, Epigenomics, 2018, vol. 10, no. 1, pp. 71—90. https://doi.org/10.2217/epi-2017-0102

    Article  CAS  PubMed  Google Scholar 

  87. Ortega-Azorín, C., Sorlí, J.V., Asensio, E.M., et al., Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low, Cardiovasc. Diabetol., 2012, vol. 1, no. 137. https://doi.org/10.1186/1475-2840-11-137

  88. Hosseini-Esfahani, F., Koochakpoor, G., Daneshpour, M.S., et al., Mediterranean dietary pattern adherence modify the association between FTO genetic variations and obesity phenotypes, Nutrients, 2017, vol. 9, no. 10. pii: E1064. https://doi.org/10.3390/nu9101064

    Article  CAS  PubMed  Google Scholar 

  89. Vimaleswaran, K.S., Bodhini, D., Lakshmipriya, N., et al., Interaction between FTO gene variants and lifestyle factors on metabolic traits in an Asian Indian population, Nutr. Metab. (London), 2016, vol. 13, no. 39. https://doi.org/10.1186/s12986-016-0098-6

  90. Lourenco, B.H., Qi, L., Willett, W.C., and Cardoso, M.A., ACTION Study Team, FTO genotype, vitamin D status, and weight gain during childhood, Diabetes, 2014, vol. 63, pp. 808—814. https://doi.org/10.2337/db13-1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bandstein, M., Schultes, B., Ernst, B., et al., The role of FTO and vitamin D for the weight loss effect of Roux-en-Y gastric bypass surgery in obese patients, Obes. Surg., 2015, vol. 25, no. 11, pp. 2071—2077. https://doi.org/10.1007/s11695-015-1644-4

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bjørnland, T., Langaas, M., Grill, V., and Mostad, I.L., Assessing gene-environment interaction effects of FTO, MC4R and lifestyle factors on obesity using an extreme phenotype sampling design: results from the HUNT study, PLoS One, 2017, vol. 12, no. 4. e0175071. https://doi.org/10.1371/journal.pone.0175071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shinozaki, K., Okuda, M., Okayama, N., and Kunitsugu, I., Physical activity modifies the FTO effect on body mass index change in Japanese adolescents, Pediatr. Int., 2018, vol. 60, no. 7, pp. 656—661. https://doi.org/10.1111/ped.13578

    Article  PubMed  Google Scholar 

  94. Graff, M., Scott, R.A., Justice, A.E., et al., Genome-wide physical activity interactions in adiposity—a meta-analysis of 200 452 adults, PLoS Genet., 2017, vol. 13, no. 4. e1006528. https://doi.org/10.1371/journal.pgen.1006528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Reddon, H., Gerstein, H.C., Engert, J.C., et al., Physical activity and genetic predisposition to obesity in a multiethnic longitudinal study, Sci. Rep., 2016, vol. 6, article 18672. https://doi.org/10.1038/srep18672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kaspi, A., Khurana, I., Ziemann, M., et al., Diet during pregnancy is implicated in the regulation of hypothalamic RNA methylation and risk of obesity in offspring, Mol. Nutr. Food Res., 2018. e1800134. https://doi.org/10.1002/mnfr.201800134

  97. Doaei, S., Kalantari, N., Mohammadi, N.K., et al., Macronutrients and the FTO gene expression in hypothalamus; a systematic review of experimental studies, Indian Heart J., 2017, vol. 69, no. 2, pp. 277—281. https://doi.org/10.1016/j.ihj.2017.01.014

    Article  PubMed  PubMed Central  Google Scholar 

  98. Przeliorz-Pyszczek, A. and Regulska-Ilow, B., The role of macronutrient intake in reducing the risk of obesity and overweight among carriers of different polymorphisms of FTO gene: a review, Rocz. Panstw. Zakl. Hig., 2017, vol. 68, no. 1, pp. 5—13.

    CAS  PubMed  Google Scholar 

  99. Khan, S.M., El Hajj Chehadeh, S., Abdulrahman, M., et al., Establishing a genetic link between FTO and VDR gene polymorphisms and obesity in the Emirati population, BMC Med. Genet., 2018, vol. 19, no. 1, p. 11. https://doi.org/10.1186/s12881-018-0522-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rivera, M., Locke, A.E., Corre, T., et al., Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals, Br. J. Psychiatry, 2017, vol. 211, no. 2, pp. 70—76. https://doi.org/10.1192/bjp.bp.116.183475

    Article  PubMed  PubMed Central  Google Scholar 

  101. Schröder, C., Czerwensky, F., Leucht, S., and Steimer, W., Fat mass and obesity-related gene variants rs9939609 and rs7185735 are associated with second-generation antipsychotic-induced weight gain, Pharmacopsychiatry, 2019, vol. 52, no. 1, pp. 16—23. https://doi.org/10.1055/s-0043-125392

    Article  CAS  PubMed  Google Scholar 

  102. Armamento-Villareal, R., Wingkun, N., Aguirre, L.E., et al., The FTO gene is associated with a paradoxically favorable cardiometabolic risk profile in frail, obese older adults, Pharmacogenet. Genomics, 2016, vol. 26, no. 4, pp. 154—160. https://doi.org/10.1097/FPC.0000000000000201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Perfilyev, A., Dahlman, I., Gillberg, L., et al., Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial, Am. J. Clin. Nutr., 2017, vol. 105, no. 4, pp. 991—1000. https://doi.org/10.3945/ajcn.116.143164

    Article  CAS  PubMed  Google Scholar 

  104. Tehranifar, P., Wu, H.C., McDonald, J.A., et al., Maternal cigarette smoking during pregnancy and offspring DNA methylation in midlife, Epigenetics, 2017, vol. 13, no. 2, pp. 129—134. https://doi.org/10.1080/15592294.2017.1325065

    Article  Google Scholar 

  105. Richmond, R.C., Suderman, M., Langdon, R., et al., DNA methylation as a marker for prenatal smoke exposure in adults, Int. J. Epidemiol., 2018, vol. 47, no. 4, pp. 1120—1130. https://doi.org/10.1093/ije/dyy091

    Article  PubMed  PubMed Central  Google Scholar 

  106. Liu, Z.W., Zhang, J.T., Cai, Q.Y., et al., Birth weight is associated with placental fat mass- and obesity-associated gene expression and promoter methylation in a Chinese population, J. Matern. Fetal. Neonatal. Med., 2016, vol. 29, no. 1, pp. 106—111. https://doi.org/10.3109/14767058.2014.987749

    Article  CAS  PubMed  Google Scholar 

  107. Mansego, M.L., Milagro, F.I., Zulet, M.A., and Martinez, J.A., SH2B1 CpG-SNP is associated with body weight reduction in obese subjects following a dietary restriction program, Ann. Nutr. Metab., 2015, vol. 66, no. 1, pp. 1—9. https://doi.org/10.1159/000368425

    Article  CAS  PubMed  Google Scholar 

  108. Rönn, T., Volkov, P., Gillberg, L., et al., Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood, Hum. Mol. Genet., 2015, vol. 24, no. 13, pp. 3792—3813. https://doi.org/10.1093/hmg/ddv124

    Article  CAS  PubMed  Google Scholar 

  109. Toperoff, G., Aran, D., Kark, J.D., et al., Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood, Hum. Mol. Genet., 2012, vol. 21, no. 2, pp. 371—383. https://doi.org/10.1093/hmg/ddr472

    Article  CAS  PubMed  Google Scholar 

  110. Toperoff, G., Kark, J.D., Aran, D., et al., Premature aging of leukocyte DNA methylation is associated with type 2 diabetes prevalence, Clin. Epigenet., 2015, vol. 7, no. 35. https://doi.org/10.1186/s13148-015-0069-1

  111. van Otterdijk, S.D., Binder, A.M., Szarc Vel Szic, K., et al., DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome, PLoS One, 2017, vol. 12, no. 7. e0180955. https://doi.org/10.1371/journal.pone.0180955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Willmer, T., Johnson, R., Louw, J., and Pheiffer, C., Blood-based DNA methylation biomarkers for type 2 diabetes: potential for clinical applications, Front. Endocrinol. (Lausanne), 2018, vol. 9, article 744. https://doi.org/10.3389/fendo.2018.00744

    Article  Google Scholar 

  113. Dayeh, T., Volkov, P., Salö, S., et al., Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion, PLoS Genet., 2014, vol. 10, no. 3. e1004160. https://doi.org/10.1371/journal.pgen.1004160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Elliott, H.R., Walia, G.K., Duggirala, A., et al., Migration and DNA methylation: a comparison of methylation patterns in type 2 diabetes susceptibility genes between Indians and Europeans, J. Diabetes Res. Clin. Metab., 2013, vol. 2, no. 6. https://doi.org/10.7243/2050-0866-2-6

  115. Bell, C.G., Finer, S., Lindgren, C.M., et al., Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus, PLoS One, 2010, vol. 5, no. 11. e14040. https://doi.org/10.1371/journal.pone.0014040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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. (London), 2017, vol. 41, no. 9, pp. 1427—1433. https://doi.org/10.1038/ijo.2017.127

    Article  CAS  Google Scholar 

  117. Gemma, C., Sookoian, S., Alvariñas, J., et al., Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns, Obesity (Silver Spring), 2009, vol. 17, no. 5, pp. 1032—1039. https://doi.org/10.1038/oby.2008.605

    Article  CAS  PubMed  Google Scholar 

  118. Almén, M.S., Jacobsson, J.A., Moschonis, G., et al., Genome wide analysis reveals association of a FTO gene variant with epigenetic changes, Genomics, 2012, vol. 99, no. 3, pp. 132—137. https://doi.org/10.1016/j.ygeno.2011.12.007

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute of Medical Genetics, National Research Medical Center, Russian Academy of Sciences, 634050, Tomsk, Russia

    A. N. Kucher

Authors
  1. A. N. Kucher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. N. Kucher.

Ethics declarations

The author declares no conflict of interest. This article does not contain any studies involving animals or human participants performed by the author.

Additional information

Translated by N. Maleeva

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kucher, A.N. The FTO Gene and Diseases: The Role of Genetic Polymorphism, Epigenetic Modifications, and Environmental Factors. Russ J Genet 56, 1025–1043 (2020). https://doi.org/10.1134/S1022795420090136

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795420090136

Keywords:

Search

Navigation