|
|
FTO Gene Association with BMI and Obesity« Back to Volume 24, Issue 1, May 2008 - Table of Contents Frayling et al and Dina et al have both linked a common variant in a set of single nucleotide polymorphisms (SNPs) in the first intron of FTO (fat mass and obesity associated gene; OMIM 610966, chromosome 16q12.2) with early onset of severe obesity in children and adults of European ancestry. FTO has 9 exons; its product and function are as yet unknown. In the report of Frayling et al, a genome-wide association study of 490,032 SNPs and their relationship to type 2 diabetes mellitus (T2DM) was conducted and 10 SNPs in intron 1 of FTO (designated A allele) was found to be closely related to this disorder. Further analysis revealed an even stronger association between BMI and the FTO intron 1 SNPs variant. In adults of all ages and both genders, each A allele was associated with an increase in BMI of 0.10 z–score units (~0.4 kg/m2). Adult carriers of one A allele had an odds ratio of 1.31 for being overweight (BMI >25 kg/m2) and of 1.18 for being obese (>30 kg/m2); subjects homozygous for the A allele had 1.38 risk of being overweight and a 1.67 risk of obesity. Similar studies in children and adolescents between 7 to 14 years of age revealed that those with one A allele had an odds ratio of 1.27 for being overweight and of 1.35 for being obese. Waist circumference, skin-fold thickness, and DEXA measurement of fat mass were increased in children with the A allele. Frayling and co-workers found no functional variants in the exonic sequences of FTO relative to the SNPs variation in intron 1. Thus, the manner in which this variant of FTO affects weight accumulation is as yet unknown. Dina et al also associated the A allele with severe obesity in adults (BMI >40 kg/m2 ) as well as with early-onset obesity in children, but found no mutations in the coding regions of FTO. Both groups concluded that a variant in SNPs in intron 1 of FTO is associated with an increased risk of obesity in children and adults, but the mechanism of the effect remains unexplained at present. Editor’s CommentExperimentally in mice, deletion of the chromosome segment in which FTO is located is embryonically lethal in the homozygotic animal and is marked by fused toes and thymic hyperplasia in the heterozygotic mouse that is of normal weight. Therefore, the composition, structure, and functional properties of the product(s) of FTO variants may need to be identified by methods other than those that attenuate (or enhance?) expression of FTO in experimental animals. If these goals can be successfully accomplished and the functional relationships between variants of FTO and the regulation of energy metabolism and conservation elucidated, then it may be possible to design agents that can be directed to sites of FTO action that will ultimately lead to improved methods of weight control. Interestingly, the presence or absence of the A allele was not associated with birth weight. David E. Sandberg, PhD Reference - (linked to
|
Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
)