FTO gene and his role in genetic determination of obesity
Authors:
D. Dlouhá; J. A. Hubáček
Authors‘ workplace:
Laboratoř pro výzkum aterosklerózy, Centrum experimentální medicíny IKEM Praha, vedoucí pracoviště prof. MUDr. Luděk Červenka, CSc., MBA
Published in:
Vnitř Lék 2012; 58(3): 208-215
Category:
Reviews
Overview
Obesity is a risk factor for development of cardiovascular disease, type 2 diabetes and some cancers. Substantial proportions of obese people die from diseases caused by complications of overweight. The incidence of obesity in different populations exceeds 15%. The emergence of obesity is influenced by external factors (especially excessive energy intake and reduced physical activity). Body Mass Index (BMI) is also influenced by genetic factors, estimates of the degree of inheritance of obesity, according to the type of study range from 30 to 70%. Newly detected genetic risk factor for body weight is the FTO gene (“fat mass and obesity associated”). Variants in the first (and in some populations also in the third) intron of this gene are associated with BMI values and the presence of one risk allele is associated with an increase of body weight by about 1.5–2 kg. Studies on the possible causality (impact on energy intake, basal metabolism, physical activity) did not show consistent results. Variants in the first intron are also associated with higher risk of type 2 diabetes, polycystic ovary syndrome, and cardiovascular disease and seem to play a role in the determination of certain types of cancer and are associated with higher mortality. The exact mechanism of the effect of FTO on BMI determination is not yet known, however, the FTO exhibit a DNA demethylase activity and its role is designed as a transcription coactivator.
Key words:
FTO – obesity – BMI – polymorphism
Sources
1. Marinou K, Tousoulis D, Antonopoulos AS et al. Obesity and cardiovascular disease: from pathophysiology to risk stratification. Int J Cardiol 2010; 138: 3–8.
2. Hainer V et al. Základy klinické obezitologie. II. přepracované a doplněné vydání. Praha: Grada publishing 2011.
3. Lizicárová D, Hirnerová E, Krahulec B. Obesity – the risk factor of cardiovascular disease in patients with chronic kidney disease? Vnitř Lék 2010; 56: 1088–1092.
4. Martín-Ponce E, Santolaria F, Alemán-Valls MR et al. Factors involved in the paradox of reverse epidemiology. Clin Nutr 2010; 29: 501–506.
5. Hubacek JA. Eat less and exercise more – is it really enough to knock down the obesity pandemia? Physiol Res 2009; 58 (Suppl 1): S1–S6.
6. Stunkard AJ, Harris JR, Pedersen NL et al. The body-mass index of twins who have been reared apart. N Engl J Med 1990; 322: 1483–1487.
7. Hainerová IA. Genetics of obesity. Vnitř Lék 2010; 56: 1035–1042.
8. Hainer V, Zamrazilová H, Spálová J et al. Role of hereditary factors in weight loss and its maintenance. Physiol Res 2008; 57 (Suppl 1): S1–S15.
9. Bogardus C. Missing heritability and GWAS utility. Obesity (Silver Spring) 2009; 17: 209–210.
10. Peters T, Ausmeier K, Rüther U. Cloning of Fatso (FTO), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm Genome 1999; 10: 983–986.
11. 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; 85: 106–111.
12. Loos RJ, Bouchard C. FTO: the first gene contributing to common forms of human obesity. Obes Rev 2008; 9: 246–250.
13. Dina C, Meyre D, Gallina S et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.
14. Frayling TM, Timpson NJ, Weedon MN et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894.
15. Fischer J, Koch L, Emmerling C et al. Inactivation of the FTO gene protects from obesity. Nature 2009; 458: 894–898.
16. Church C, Lee S, Bagg EA et al. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet 2009; 5: e1000599.
17. Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends Genet 2010; 26: 266–274.
18. Gerken T, Girard CA, Tung YC et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007; 318: 1469–1472.
19. Jia G, Yang CG, 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; 582: 3313–3319.
20. Wu Q, Saunders RA, Szkudlarek-Mikho M et al. The obesity-associated FTO gene is a transcriptional coactivator. Biochem Biophys Res Commun 2010; 401: 390–395.
21. Scuteri A, Sanna S, Chen WM et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity related traits. PLoS Genet 2007; 3: e115.
22. Hubacek JA, Pitha J, Adamkova V et al. A common variant in the FTO gene is associated with body mass index in males and postmenopausal females but not in premenopausal females. Czech post-MONICA and 3PMFs studies. Clin Chem Lab Med 2009; 47: 387–390.
23. Jacobsson JA, Danielsson P, Svensson V et al. Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes. Biochem Biophys Res Commun 2008; 368: 476–482.
24. Song Y, You NC, Hsu YH et al. FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women. Obesity (Silver Spring) 2008; 16: 2472–2480.
25. Bollepalli S, Dolan LM, Deka R et al. Association of FTO gene variants with adiposity in African-American adolescents. Obesity (Silver Spring) 2010; 18: 1959–1963.
26. López-Bermejo A, Petry CJ, Díaz M et al. The association between the FTO gene and fat mass in humans develops by the postnatal age of two weeks. J Clin Endocrinol Metab 2008; 93: 1501–1505.
27. Liu G, Zhu H, Lagou V et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African- American youth. BMC Med Genet 2010; 11: 57.
28. Rendo T, Moleres A, Marti Del Moral A. Effects of the FTO gene on lifestyle intervention studies in children. Obes Facts 2009; 2: 393–399.
29. Demerath EW, Lutsey PL, Monda KL et al. Interaction of FTO and physical activity level on adiposity in African-American and European-American adults: the ARIC Study. Obesity (Silver Spring) 2011; 19: 1866–1872.
30. Liu Y, Liu Z, Song Y et al. Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. Obesity (Silver Spring) 2010; 18: 1619–1624.
31. Cheung CY, Tso AW, Cheung BM et al. Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population. J Clin Endocrinol Metab 2010; 95: 1395–1403.
32. Adeyemo A, Chen G, Zhou J et al. FTO genetic variation and association with obesity in West Africans and African Americans. Diabetes 2010; 59: 1549–1554.
33. Tönjes A, Zeggini E, Kovacs P et al. Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany. Eur J Hum Genet 2010; 18: 104–110.
34. Dlouha D, Adamkova V, Lanska V et al. Lack of association between a new tag SNP in the FTO gene and BMI in Czech-Slavonic population. Eur J Hum Genet 2010; 18: 1274.
35. Meyre D, Proulx K, Kawagoe-Takaki H et al. Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes 2010; 59: 311–318.
36. Berentzen T, Kring SI, Holst C et al. Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. J Clin Endocrinol Metab 2008; 93: 2904–2908.
37. Müller TD, Hinney A, Scherag A et al. Fat mass and obesity associated gene (FTO): no significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolizm markers in German obese children and adolescents. BMC Med Genet 2008; 9: 85.
38. Lappalainen TJ, Tolppanen AM, Kolehmainen M et al. Diabetes Prevention Study Group. The common variant in the FTO gene did not modify the effect of lifestyle changes on body weight: the Finnish Diabetes Prevention Study. Obesity (Silver Spring) 2009; 17: 832–836.
39. Hakanen M, Raitakari OT, Lehtimäki T et al. FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity. J Clin Endocrinol Metab 2009; 94: 1281–1287.
40. Johnson L, van Jaarsveld CH, Emmett PM et al. Dietary energy density affects fat mass in early adolescence and is not modified by FTO variants. PLoS One 2009; 4: e4594.
41. Hasselbalch AL, Angquist L, Christiansen L et al. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake. J Nutr 2010; 140: 831–834.
42. Dlouha D, Suchanek P, Lanska V et al. Body mass index change in females after short-time life style intervention is not dependent on the FTO polymorphisms. Physiol Res 2011; 60: 199–202.
43. Cecil JE, Tavendale R, Watt P et al. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008; 359: 2558–2566.
44. Haupt A, Thamer C, Staiger H et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes 2009; 117: 194–197.
45. Timpson NJ, Emmett PM, Frayling TM et al. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr 2008; 88: 971–978.
46. Wardle J, Llewellyn C, Sanderson S et al. The FTO gene and measured food intake in children. Int J Obes (Lond) 2009; 33: 42–45.
47. Andreasen CH, Stender-Petersen KL, Mogensen MS et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 2008; 57: 95–101.
48. WÅhlén K, Sjölin E, Hoffstedt J. The common rs9939609 gene variant of the fat mass and obesity associated gene (FTO) is related to fat cell lipolysis. J Lipid Res 2008; 49: 607–611.
49. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring) 2008; 16: 1961–1965.
50. Do R, Bailey SD, Desbiens K et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes 2008; 57: 1147–1150.
51. Hubacek JA, Pikhart H, Peasey A et al. FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. The HAPIEE study. Physiol Res 2011; 60: 175–183.
52. Legry V, Cottel D, Ferrières J et al. Effect of an FTO polymorphism on fat mass, obesity, and type 2 diabetes mellitus in the French MONICA Study. Metabolism 2009; 58: 971–975.
53. Scott LJ, Mohlke KL, Bonnycastle LL et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007; 316: 1341–1345.
54. Burton PR, Clayton DG, Cardon LR et al. The Wellcome Trust Case-Control Consortium. Genome-wide associationstudy of 14,000 cases of seven common diseases and 3,000 shared--controls. Nature 2007; 447: 661–678.
55. Bravard A, Lefai E, Meugnier E et al. FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. Diabetes 2011; 60: 258–268.
56. Rees SD, Islam M, Hydrie MZ et al. An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabet Med 2011; 28: 673–680.
57. Hertel JK, Johansson S, Sonestedt E et al. FTO, type 2 diabetes and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC and MPP studies. Diabetes 2011; 60: 1637–1644.
58. Takeuchi F, Yamamoto K, Katsuya T et al. Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals. Diabetologia 2011; 54: 1350–1359.
59. Ramya K, Radha V, Ghosh S et al. Genetic variations in the FTO gene are associated with type 2 diabetes and obesity in south Indians (CURES-79). Diabetes Technol Ther 2011; 13: 33–42.
60. Doney AS, Dannfald J, Kimber CH et al. The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes: a Genetics of Diabetes Audit and Research Study in Tayside Scotland (Go-DARTS) study. Circ Cardiovasc Genet 2009; 2: 255–259.
61. Lappalainen T, Kolehmainen M, Schwab US et al. Finnish Diabetes Prevention Study Group. Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolizm – The Finnish Diabetes Prevention Study. Nutr Metab Cardiovasc Dis 2011; 21: 691–698.
62. Hubacek JA, Stanek V, Gebauerová M et al. A FTO variant and risk of acute coronary syndrome. Clin Chim Acta 2010; 411: 1069–1072.
63. Ahmad T, Chasman DI, Mora S et al. The fat-mass and obesity-associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am Heart J 2010; 160: 1163–1169.
64. Brennan P, McKay J, Moore L et al. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. Int J Epidemiol 2009; 38: 971–975.
65. Gaudet MM, Yang HP, Bosquet JG et al. No association between FTO or HHEX and endometrial cancer risk. Cancer Epidemiol Biomarkers Prev 2010; 19: 2106–2109.
66. Lurie G, Gaudet MM, Spurdle AB et al. Australian National Endometrial Cancer Study Group; Epidemiology of Endometrial Cancer Consortium (E2C2). The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PLoS One 2011; 6: e16756.
67. Lewis SJ, Murad A, Chen L, et al. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS One 2010; 5: e13485.
68. Nock NL, Plummer SJ, Thompson CL et al. FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans. Carcinogenesis 2011; 32: 748–756.
69. Asunción M, Calvo RM, San Millán JL et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000; 85: 2434–2438.
70. Legro RS. The genetics of obesity. Lessons for polycystic ovary syndrome. Ann NY Acad Sci 2000; 900: 193–202.
71. Barber TM, Bennett AJ, Groves CJ et al. Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia 2008; 51: 1153–1158.
72. Attaoua R, Ait El, Mkadem S et al. FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochem Biophys Res Commun 2008; 373: 230–234.
73. Hubacek JA, Viklicky O, Dlouha D et al. The FTO gene polymorphism is associated with end-stage renal disease: two large independent case--control studies in a general population. Nephrol Dial Transplant 2012; 27: 1030–1035.
74. Bassols J, Prats-Puig A, Vázquez-Ruíz M et al. Placental FTO expression relates to fetal growth. Int J Obes (Lond) 2010; 34: 1365–1370.
75. Zimmermann E, Kring SI, Berentzen TL et al. Fatness-associated FTO gene variant increases mortality independent of fatness – in cohorts of Danish men. PLoS One 2009; 4: e4428.
76. Sonestedt E, Gullberg B, Ericson U et al. Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int J Obes (Lond) 2011; 35: 1041–1049.
77. Holzapfel C, Grallert H, Huth C et al. Genes and lifestyle factors in obesity: results from 12,462 subjects from MONICA/KORA. Int J Obes (Lond) 2010; 34: 1538–1545.
78. Shimaoka I, Kamide K, Ohishi M et al. Association of gene polymorphism of the fat-mass and obesity-associated gene with insulin resistance in Japanese. Hypertens Res 2010; 33: 214–218.
79. Bierut LJ, Madden PA, Breslau N et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16: 24–35.
80. Sobczyk-Kopciol A, Broda G, Wojnar M et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 2011; 106: 739–748.
81. Hubacek JA, Dlouha D, Lanska V et al. Lack of an association between three tagging SNPs within the FTO gene and smoking behavior. Nicotine Tob Res 2011 [Epub ahead of print].
82. Hunt SC, Stone S, Xin Y et al. Association of the FTO gene with BMI. Obesity (Silver Spring) 2008; 16: 902–904.
83. Cornes BK, Lind PA, Medland SE et al. Replication of the association of common rs9939609 variant of FTO with increased BMI in an Australian adult twin population but no evidence for gene by environment (G × E) interaction. Int J Obes (Lond) 2009; 33: 75–79.
84. Mei H, Chen W, Srinivasan SR et al. FTO influences on longitudinal BMI over childhood and adulthood and modulation on relationship between birth weight and longitudinal BMI. Hum Genet 2010; 128: 589–596.
85. Ruiz JR, Labayen I, Ortega FB et al. HELENA Study Group. Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study. Arch Pediatr Adolesc Med 2010; 164: 328–333.
86. Rutters F, Nieuwenhuizen AG, Bouwman F et al. Associations between a single nucleotide polymorphism of the FTO gene (rs9939609) and obesity-related characteristics over time during puberty in a dutch children cohort. J Clin Endocrinol Metab 2011; 96: E939–E942.
87. Kivimäki M, Jokela M, Hamer M et al. Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: The Whitehall II Study, 1985–2004. Am J Epidemiol 2011; 173: 421–429.
88. Mook-Kanamori DO, Ay L, Hofman A et al. No association of obesity gene FTO with body composition at the age of 6 months. The Generation R Study. J Endocrinol Invest 2011; 34: 16–20.
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