The FTO Gene and Diseases: The Role of Genetic Polymorphism, Epigenetic Modifications, and Environmental Factors
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EWS AND THEORETICAL ARTICLES
The FTO Gene and Diseases: The Role of Genetic Polymorphism, Epigenetic Modifications, and Environmental Factors A. N. Kuchera, * a
Research Institute of Medical Genetics, National Research Medical Center, Russian Academy of Sciences, Tomsk, 634050 Russia *e-mail: [email protected]
Received November 6, 2019; revised December 4, 2019; accepted December 17, 2019
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. Keywords: FTO gene, polymorphisms, associations of polymorphisms with diseases, epigenetics, modifying environmental factors DOI: 10.1134/S1022795420090136
INTRODUCTION The FTO gene was discovered in 1999 by T. Peters et al. [1], who, owing to the large size of the gene (at least 250 kb), called it Fatso (Fto). Later, this designation was associated with frequently detected association of polymorphisms within this gene with body mass index and obesity. Because
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