FTO gene

A study of 38,759 Europeans for variants of FTO identified an obesity risk allele.^[1] In particular, carriers of one copy of the allele weighed on average 1.2 kg more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 kg more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is also associated with increased risk of Type 2 Diabetes.

The authors of this study claim that while obesity was already known to have a genetic component (from twin studies), no replicated previous study has ever identified a obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese.

Furthermore morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.^[2]

[edit] Association with other diseases

The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL-cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index.^[3]

[edit] Origin of name

The gene's abbreviation is FTO because a deletion in a homologous region in mice results in fused toes (FT) and other abnormalities.^[4] The gene name "Fatso" was given in 1999, before its association with obesity was known.

[edit] Function

The amino acid sequence of the transcribed FTO protein shows high homology with the enzyme AlkB which oxidatively demethylates DNA.^[5]^[6] Furthermore recombinant FTO protein catalyzes demethylation of 3-methylthymine in single-stranded DNA.^[5] The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexin peptide which is involved in the stimulation of food intake.^[7]

[edit] Tissue distribution

The FTO gene is widely expressed in both fetal and adult tissue, however it has especially high expression in the hypothalamus and pancreatic islets.^[1]

[edit] References

^ ^a ^b Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI (2007). "A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity". Science 316 (5826): 889–94. doi:10.1126/science.1141634. PMID 17434869.
^ Chu X, Erdman R, Susek M, Gerst H, Derr K, Al-Agha M, Wood GC, Hartman C, Yeager S, Blosky MA, Krum W, Stewart WF, Carey D, Benotti P, Still CD, Gerhard GS (2008). "Association of morbid obesity with FTO and INSIG2 allelic variants". Arch Surg 143 (3): 235–40; discussion 241. doi:10.1001/archsurg.2007.77. PMID 18347269.
^ Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A, Ebrahim S, Shields B, Zeggini E, Weedon MN, Lindgren CM, Lango H, Melzer D, Ferrucci L, Paolisso G, Neville MJ, Karpe F, Palmer CN, Morris AD, Elliott P, Jarvelin MR, Smith GD, McCarthy MI, Hattersley AT, Frayling TM (2008). "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI". Diabetes. doi:10.2337/db07-1466. PMID 18346983.
^ Peters T, Ausmeier K, Rüther U (1999). "Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation". Mamm. Genome 10 (10): 983–6. doi:10.1007/s003359901144. PMID 10501967.
^ ^a ^b Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ (2007). "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase". Science 318 (5855): 1469–72. doi:10.1126/science.1151710. PMID 17991826.
^ Sanchez-Pulido L, Andrade-Navarro MA (2007). "The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily". BMC Biochem. 8: 23. doi:10.1186/1471-2091-8-23. PMID 17996046.
^ Fredriksson R, Hägglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schiöth HB (2008). "The obesity gene, FTO, is of ancient origin, upregulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain". Endocrinology. doi:10.1210/en.2007-1457. PMID 18218688.