Abstract
Single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene reported in 2007 continue to be the known variants with the greatest effect on adiposity in different human populations. Coding variants in the FTO gene, on the other hand, have been little explored, although data from complete sequencing of the exomes of various populations are available in public databases and provide an excellent opportunity to investigate potential functional variants in FTO. In this context, this study aimed to track nonsynonymous variants in the exons of the FTO gene in different population groups employing the gnomAD database and analyze the potential functional impact of these variants on the FTO protein using five publicly available pathogenicity prediction programs. The findings revealed 345 rare mutations, of which 321 are missense (93%), 19 are stop gained (5.6%) and five mutations are located in the splice region (1.4%). Of these, 134 (38.8%) were classified as pathogenic, 144 (41.7%) as benign and 67 (19.5%) as unknown. The available data, however, suggest that these variants are probably not associated with BMI and obesity, but instead, with other diseases. Functional studies are, therefore, required to identify the role of these variants in disease genesis.
Highlights
The Fat mass and obesity-associated gene, known as FTO, was the first obesity susceptibility gene identified through Genome-Wide Association Studies (GWAS) and remains the locus with the greatest effect on adiposity in different human populations
Four independent GWAS published in 2007 reported a significant association between body mass index and body fat and common genetic FTO gene variants, a group of single nucleotide polymorphisms (SNPs) in the first intron of this gene
Information on the position, nucleotide change, amino acid change, type of mutation, allele count, number of alleles and frequency of each variant in Latino/Admixed American, South Asian, East Asian, African/African-American, European and European (Finnish) populations is presented in S1 Table
Summary
The Fat mass and obesity-associated gene, known as FTO (alpha-ketoglutarate-dependent dioxygenase), was the first obesity susceptibility gene identified through Genome-Wide Association Studies (GWAS) and remains the locus with the greatest effect on adiposity in different human populations. The FTO was identified for the first time in Europeans in 2007 [1], and shortly thereafter, its association with BMI and obesity risk was confirmed by three other studies [2,3,4]. This association has been replicated in other populations (Asians, Hispanics and Native Americans), conflicting results have been observed in African/African-American populations [5, 6].
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