Influence of FTO variants on obesity, inflammation and cardiovascular disease risk biomarkers in Spanish children: A case-control multicentre study

BMC Medical Genetics

Volumn 14, Issue 1, 2013, Pages

  Olza, Josune ^a   Ruperez, Azahara I ^a   Gil Campos, Mercedes ^b   Leis, Rosaura ^c   Fernandez Orth, Dietmar ^d   Tojo, Rafael ^c   Cañete, Ramon ^b   Gil, Angel ^a   Aguilera, Concepcion M ^a  

^a UNIVERSITY OF GRANADA   (Spain)

^b HOSPITAL UNIVERSITARIO REINA SOFÍA   (Spain)

^c Instituto de Salud Carlos III   (Spain)

^d Progenika Biopharma SA   (Spain)

Author keywords

Child; CVD; FTO; Genetic polymorphism; Inflammation; Obesity

Indexed keywords

ADIPONECTIN; APOLIPOPROTEIN A1; APOLIPOPROTEIN B; C REACTIVE PROTEIN; GELATINASE B; HIGH DENSITY LIPOPROTEIN; INSULIN; INTERLEUKIN 6; INTERLEUKIN 8; LEPTIN; LOW DENSITY LIPOPROTEIN; METALLOPROTEINASE; SELECTIN; TUMOR NECROSIS FACTOR ALPHA;

ADOLESCENT; ALLELE; ANTHROPOMETRIC PARAMETERS; ARTICLE; BODY MASS; CARDIOVASCULAR RISK; CASE CONTROL STUDY; CHILD; CHILDHOOD DISEASE; CONTROLLED STUDY; FAT MASS AND OBESITY ASSOCIATED GENE; FEMALE; GENE; GENE LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; GLUCOSE BLOOD LEVEL; HAPLOTYPE; HUMAN; INFLAMMATION; INSULIN RESISTANCE; MAJOR CLINICAL STUDY; MALE; METABOLIC PARAMETERS; MULTICENTER STUDY; OBESITY; PROTEIN BLOOD LEVEL; SINGLE NUCLEOTIDE POLYMORPHISM; SPAIN;

ADOLESCENT; ALLELES; BIOLOGICAL MARKERS; CARDIOVASCULAR DISEASES; CASE-CONTROL STUDIES; CHILD; EUROPEAN CONTINENTAL ANCESTRY GROUP; FEMALE; GENOTYPE; HAPLOTYPES; HUMANS; INFLAMMATION; INTRONS; LEPTIN; LINKAGE DISEQUILIBRIUM; MALE; OBESITY; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEINS; RISK FACTORS; SPAIN;

EID: 84888338177     PISSN: None     EISSN: 14712350     Source Type: Journal    
DOI: 10.1186/1471-2350-14-123     Document Type: Article

References (49)

1. Pietrobelli A, Espinoza MC, De Cristofaro P. Childhood obesity: looking into the future. Angiology 2008, 59:30S-33S. 10.1177/0003319708318788, 18504263.
2. Abrams P, Levitt Katz LE. Metabolic effects of obesity causing disease in childhood. Curr Opin Endocrinol Diabetes Obes 2011, 18:23-27. 10.1097/MED.0b013e3283424b37, 21157321.
3. 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, 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. 10.1126/science.1141634, 2646098, 17434869.
4. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007, 39:724-726. 10.1038/ng2048, 17496892.
5. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007, 3:1200-1210.
6. Peng S, Zhu Y, Xu F, Ren X, Li X, Lai M. FTO gene polymorphisms and obesity risk: a meta-analysis. BMC Med 2011, 9:71. 10.1186/1741-7015-9-71, 3118373, 21651756.
7. Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H, Hebebrand J. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007, 2:e1361. 10.1371/journal.pone.0001361, 2137937, 18159244.
8. Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP, Hopkins PN, Adams TD. Association of the FTO gene with BMI. Obesity 2008, 16:902-904. 10.1038/oby.2007.126, 18239580.
9. Labayen I, Ruiz JR, Ortega FB, Gottrand F, Huybrechts I, Dallongeville J, Widhalm K, Ferrari M, Buyken A, Kersting M, Moschonis G, Turck D, Gómez S, Sjostrom M, Meirhaeghe A, Moreno LA. Body size at birth modifies the effect of fat mass and obesity associated (FTO) rs9939609 polymorphism on adiposity in adolescents: the healthy lifestyle in Europe by nutrition in adolescence (HELENA) study. Br J Nutr 2008, 107:1498-1504.
10. Xi B, Shen Y, Zhang M, Liu X, Zhao X, Wu L, Cheng H, Hou D, Lindpaintner K, Liu L, Mi J, Wang X. The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing. China. BMC Med Genet 2010, 11:107.
11. Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A, Ma G. Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 2010, 11:136. 10.1186/1471-2350-11-136, 2955568, 20858286.
12. Hassanein MT, Lyon HN, Nguyen TT, Akylbekova EL, Waters K, Lettre G, Tayo B, Forrester T, Sarpong DF, Stram DO, Butler JL, Wilks R, Liu J, Le Marchand L, Kolonel LN, Zhu X, Henderson B, Cooper R, McKenzie C, Taylor HA, Haiman CA, Hirschhorn JN. Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet 2010, 19:2907-2916. 10.1093/hmg/ddq178, 2893809, 20430937.
13. Wing MR, Ziegler J, Langefeld CD, Ng MC, Haffner SM, Norris JM, Goodarzi MO, Bowden DW. Analysis of FTO gene variants with measures of obesity and glucose homeostasis in the IRAS Family Study. Hum Genet 2009, 125:615-626. 10.1007/s00439-009-0656-3, 2792578, 19322589.
14. Rutters F, Nieuwenhuizen AG, Bouwman F, Mariman E, Westerterp-Plantenga MS. 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 2009, 96:E939-E942.
15. Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, Dong Y, Snieder H. 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. 2864242, 20377915.
16. Grant SF, Li M, Bradfield JP, Kim CE, Annaiah K, Santa E, Glessner JT, Casalunovo T, Frackelton EC, Otieno FG, Shaner JL, Smith RM, Imielinski M, Eckert AW, Chiavacci RM, Berkowitz RI, Hakonarson H. Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS One 2008, 3:e1746. 10.1371/journal.pone.0001746, 2262153, 18335027.
17. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 2000, 320:1240-1243. 10.1136/bmj.320.7244.1240, 27365, 10797032.
18. González JR, Armengol L, Solé X, Guinó E, Mercader JM, Estivill X, Moreno V. SNPassoc: an R package to perform whole genome association studies. Bioinformatics 2007, 23:644-645.
19. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CAN. An obesity-associated FTO gene variant and increased energy intake in children. New Eng J Med 2008, 359:2558-2566. 10.1056/NEJMoa0803839, 19073975.
20. Heard-Costa NL, Zillikens MC, Monda KL, Johansson A, Harris TB, Fu M, Haritunians T, Feitosa MF, Aspelund T, Eiriksdottir G, Garcia M, Launer LJ, Smith AV, Mitchell BD, McArdle PF, Shuldiner AR, Bielinski SJ, Boerwinkle E, Brancati F, Demerath EW, Pankow JS, Arnold AM, Chen YD, Glazer NL, McKnight B, Psaty BM, Rotter JI, Amin N, Campbell H, Gyllensten U, et al. NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet 2009, 5:e1000539. 10.1371/journal.pgen.1000539, 2695005, 19557197.
21. Wang K, Li WD, Zhang CK, Wang Z, Glessner JT, Grant SF, Zhao H, Hakonarson H, Price RA. A genome-wide association study on obesity and obesity-related traits. PLoS One 2011, 6:e18939. 10.1371/journal.pone.0018939, 3084240, 21552555.
22. Ruiz JR, Labayen I, Ortega FB, Legry V, Moreno LA, Dallongeville J, Martínez-Gómez D, Bokor S, Manios Y, Ciarapica D, Gottrand F, De Henauw S, Molnár D, Sjöström M, Meirhaeghe A, 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. 10.1001/archpediatrics.2010.29, 20368485, HELENA Study Group.
23. Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec family study. Diabetes 2008, 57:1147-1150. 10.2337/db07-1267, 18316358.
24. Belo VA, Souza-Costa DC, Luizon MR, Lanna CM, Carneiro PC, Izidoro-Toledo TC, Ferraz KC, Tanus-Santos JE. Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children. Int J Obes 2011, 36:69-75.
25. 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. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes 2008, 57:1419-1426. 10.2337/db07-1466, 3073395, 18346983.
26. Kring SI, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O, Sørensen TI. FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS One 2008, 3:e2958. 10.1371/journal.pone.0002958, 2493033, 18698412.
27. Müller TD, Hinney A, Scherag A, Nguyen TT, Schreiner F, Schäfer H, Hebebrand J, Roth CL, Reinehr T. Fat mass and obesity associated' gene (FTO): no significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents. BMC Med Genet 2008, 9:85. 2553771, 18799002.
28. Zavattari P, Loche A, Pilia S, Ibba A, Moi L, Guzzetti C, Casini MR. Loche S: rs9939609 in the FTO gene is associated with obesity but not with several biochemical parameters in Sardinian obese children. Ann Hum Genet 2011, 75:648-654. 10.1111/j.1469-1809.2011.00674.x, 21913894.
29. Ahmad T, Chasman DI, Mora S, Paré G, Cook NR, Buring JE, Ridker PM, Lee IM. 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. 10.1016/j.ahj.2010.08.002, 3058560, 21146673.
30. Lappalainen T, Kolehmainen M, Schwab US, Tolppanen AM, Stančáková A, Lindström J, Eriksson JG, Keinänen-Kiukaanniemi S, Aunola S, Ilanne-Parikka P, Herder C, Koenig W, Gylling H, Kolb H, Tuomilehto J, Kuusisto J, Uusitupa M. Finnish diabetes prevention study group: association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism--the Finnish diabetes prevention study. Nutr Metab Cardiovasc Dis 2011, 21:691-698. 10.1016/j.numecd.2010.01.006, 20400278.
31. Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjærg-Hansen A, Smith GD. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes 2011, 35:300-308.
32. Fisher E, Schulze MB, Stefan N, Häring HU, Döring F, Joost HG, Al-Hasani H, Boeing H, Pischon T. Association of the FTO rs9939609 single nucleotide polymorphism with C-reactive protein levels. Obesity 2009, 17:330-334. 10.1038/oby.2008.465, 18948966.
33. Zimmermann E, Skogstrand K, Hougaard DM, Astrup A, Hansen T, Pedersen O, Sørensen TI, Jess T. Influences of the common FTO rs9939609 variant on inflammatory markers throughout a broad range of body mass index. PLoS One 2011, 6:e15958. 10.1371/journal.pone.0015958, 3016333, 21246032.
34. Al-Attar SA, Pollex RL, Ban MR, Young TK, Bjerregaard P, Anand SS, Yusuf S, Zinman B, Harris SB, Hanley AJ, Connelly PW, Huff MW, Hegele RA. Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multiethnic sample. Cardiovasc Diabetol 2008, 7:5. 10.1186/1475-2840-7-5, 2275229, 18339204.
35. Attaoua R, Ait El Mkadem S, Lautier C, Kaouache S, Renard E, Brun JF, Fedou C, Gris JC, Bringer J, Grigorescu F. Association of the FTO gene with obesity and the metabolic syndrome is independent of the IRS-2 gene in the female population of Southern France. Diabetes Metab 2009, 35:476-483. 10.1016/j.diabet.2009.07.002, 19818665.
36. Shimaoka I, Kamide K, Ohishi M, Katsuya T, Akasaka H, Saitoh S, Sugimoto K, Oguro R, Congrains A, Fujisawa T, Shimamoto K, Ogihara T, Rakugi H. Association of gene polymorphism of the fat-mass and obesity-associated gene with insulin resistance in Japanese. Hypertens Res 2010, 33:214-218. 10.1038/hr.2009.215, 20075932.
37. Ranjith N, Pegoraro RJ, Shanmugam R. Obesity-associated genetic variants in young Asian Indians with the metabolic syndrome and myocardial infarction. Cardiovasc J Afr 2011, 22:25-30. 3736384, 21298202.
38. Luczynski W, Zalewski G, Bossowski A. The association of the FTO rs9939609 polymorphism with obesity and metabolic risk factors for cardiovascular diseases in Polish children. J Physiol Pharmacol 2012, 63:241-248.
39. Pausova Z, Syme C, Abrahamowicz M, Xiao Y, Leonard GT, Perron M, Richer L, Veillette S, Smith GD, Seda O, Tremblay J, Hamet P, Gaudet D, Paus T. A common variant of the FTO gene is associated with not only increased adiposity but also elevated blood pressure in French Canadians. Circ Cardiovasc Genet 2009, 2:260-269. 10.1161/CIRCGENETICS.109.857359, 20031594.
40. Melka MG, Bernard M, Mahboubi A, Abrahamowicz M, Paterson AD, Syme C, Lourdusamy A, Schumann G, Leonard GT, Perron M, Richer L, Veillette S, Gaudet D, Paus T, Pausova Z. Genome-wide scan for Loci of adolescent obesity and their relationship with blood pressure. J Clin Endocrinol Metab 2011, 97:E145-E150.
41. Haworth CM, Carnell S, Meaburn EL, Davis OS, Plomin R, Wardle J. Increasing heritability of BMI and stronger associations with the FTO gene over childhood. Obesity 2008, 16:2663-2668. 10.1038/oby.2008.434, 18846049.
42. Hardy R, Wills AK, Wong A, Elks CE, Wareham NJ, Loos RJ, Kuh D, Ong KK. Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 2010, 19:545-552. 10.1093/hmg/ddp504, 2798720, 19880856.
43. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010, 42:937-948. 10.1038/ng.686, 3014648, 20935630.
44. Tönjes A, Zeggini E, Kovacs P, Böttcher Y, Schleinitz D, Dietrich K, Morris AP, Enigk B, Rayner NW, Koriath M, Eszlinger M, Kemppinen A, Prokopenko I, Hoffmann K, Teupser D, Thiery J, Krohn K, McCarthy MI, Stumvoll M. 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. 10.1038/ejhg.2009.107, 2987177, 19584900.
45. Dlouha D, Adamkova V, Lanska V, Hubacek JA. 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. 10.1038/ejhg.2010.122, 3002856, 20664633.
46. Varela L, Horvath TL. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 2012, 13:1079-1086. 10.1038/embor.2012.174, 3512417, 23146889.
47. Paz-Filho G, Mastronardi C, Franco CB, Wang KB, Wong ML, Licinio J. Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications. Arq Bras Endocrinol Metabol 2012, 56:597-607. 10.1590/S0004-27302012000900001, 23329181.
48. Berglund ED, Vianna CR, Donato J, Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P, Brule LJ, Scott MM, Coppari R, Elmquist JK. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 2012, 122:1000-1009. 10.1172/JCI59816, 3287225, 22326958.
49. Esteghamati A, Khalilzadeh O, Anvari M, Rashidi A, Mokhtari M, Nakhjavani M. Association of serum leptin levels with homeostasis model assessment-estimated insulin resistance and metabol- ic syndrome: the key role of central obesity. Metab Syndr Relat Disord 2009, 7:447-452. 10.1089/met.2008.0100, 19419266.