Common genetic variation in obesity, lipid transfer genes and risk of Metabolic Syndrome: Results from IDEFICS/I.Family study and meta-analysis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Polymorphism, Single Nucleotide*; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/*genetics ; Cholesterol Ester Transfer Proteins/*genetics ; Chromosomes, Human, Pair 16/*genetics ; Metabolic Syndrome/*genetics ; Pediatric Obesity/*genetics; Adult ; Child ; Child, Preschool ; Family ; Female ; Humans ; Male ; Risk Factors

As the prevalence of metabolic syndrome (MetS) in children and young adults is increasing, a better understanding of genetics that underlie MetS will provide critical insights into the origin of the disease. We examined associations of common genetic variants and repeated MetS score from early childhood to adolescence in a pan-European, prospective IDEFICS/I.Family cohort study with baseline survey and follow-up examinations after two and six years. We tested associations in 3067 children using a linear mixed model and confirmed the results with meta-analysis of identified SNPs. With a stringent Bonferroni adjustment for multiple comparisons we obtained significant associations(p < 1.4 × 10 ^-4 ) for 5 SNPs, which were in high LD (r ²  > 0.85) in the 16q12.2 non-coding intronic chromosomal region of FTO gene with strongest association observed for rs8050136 (effect size(β) = 0.31, p Wald  = 1.52 × 10 ^-5 ). We also observed a strong association of rs708272 in CETP with increased HDL (p = 5.63 × 10 ^-40 ) and decreased TRG (p = 9.60 × 10 ^-5 ) levels. These findings along with meta-analysis advance etiologic understanding of childhood MetS, highlighting that genetic predisposition to MetS is largely driven by genes of obesity and lipid metabolism. Inclusion of the associated genetic variants in polygenic scores for MetS may prove to be fundamental for identifying children and subsequently adults of the high-risk group to allow earlier targeted interventions.

Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640–1645, https://doi.org/10.1161/circulationaha.109.192644 (2009). (PMID: 10.1161/circulationaha.109.1926441980565419805654)
Grundy, S. M. Metabolic syndrome pandemic. Arteriosclerosis, thrombosis, Vasc. Biol. 28, 629–636, https://doi.org/10.1161/atvbaha.107.151092 (2008). (PMID: 10.1161/atvbaha.107.151092)
Henneman, P. et al. Genetic architecture of plasma adiponectin overlaps with the genetics of metabolic syndrome-related traits. Diabetes Care 33, 908–913, https://doi.org/10.2337/dc09-1385 (2010). (PMID: 10.2337/dc09-1385200679572845050)
Monda, K. L. et al. The genetics of obesity and the metabolic syndrome. Endocr. Metab. Immune Disord. Drug. Targets 10, 86–108 (2010). (PMID: 10.2174/187153010791213100)
Lee, H. S., Kim, Y. & Park, T. New Common and Rare Variants Influencing Metabolic Syndrome and Its Individual Components in a Korean Population. Sci. Rep. 8, 5701, https://doi.org/10.1038/s41598-018-23074-2 (2018). (PMID: 10.1038/s41598-018-23074-2296323055890262)
Jeong, S. W., Chung, M., Park, S. J., Cho, S. B. & Hong, K. W. Genome-wide association study of metabolic syndrome in koreans. Genomics Inf. 12, 187–194, https://doi.org/10.5808/GI.2014.12.4.187 (2014). (PMID: 10.5808/GI.2014.12.4.187)
Zhu, Y. et al. Susceptibility loci for metabolic syndrome and metabolic components identified in Han Chinese: a multi-stage genome-wide association study. J. Cell Mol. Med. 21, 1106–1116, https://doi.org/10.1111/jcmm.13042 (2017). (PMID: 10.1111/jcmm.13042283713265431133)
Kristiansson, K. et al. Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits. Circ. Cardiovasc. Genet. 5, 242–249, https://doi.org/10.1161/CIRCGENETICS.111.961482 (2012). (PMID: 10.1161/CIRCGENETICS.111.961482223995273378651)
McGarry, J. D. Banting Lecture 2001. Dysregulation Fat. Acid. Metab. Etiology Type 2 Diabetes 51, 7–18, https://doi.org/10.2337/diabetes.51.1.7 (2002). (PMID: 10.2337/diabetes.51.1.7)
Kraja, A. T. et al. A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. Diabetes 60, 1329–1339, https://doi.org/10.2337/db10-1011 (2011). (PMID: 10.2337/db10-1011213860853064107)
Aguilera, C. M., Olza, J. & Gil, A. Genetic susceptibility to obesity and metabolic syndrome in childhood. Nutr. Hosp. 28(Suppl 5), 44–55, https://doi.org/10.3305/nh.2013.28.sup5.6917 (2013). (PMID: 10.3305/nh.2013.28.sup5.691724010743)
Penas-Steinhardt, A. et al. Association of common variants in JAK2 gene with reduced risk of metabolic syndrome and related disorders. BMC Med. Genet. 12, 166, https://doi.org/10.1186/1471-2350-12-166 (2011). (PMID: 10.1186/1471-2350-12-166221856743259043)
Hou, H. et al. Association between Six CETP Polymorphisms and Metabolic Syndrome in Uyghur Adults from Xinjiang, China. Int J Environ Res Public Health 14, https://doi.org/10.3390/ijerph14060653 (2017).
Cahua-Pablo, J. A. et al. Polymorphisms in the LPL and CETP Genes and Haplotype in the ESR1 Gene Are Associated with Metabolic Syndrome in Women from Southwestern Mexico. Int. J. Mol. Sci. 16, 21539–21554, https://doi.org/10.3390/ijms160921539 (2015). (PMID: 10.3390/ijms160921539263709764613266)
Al-Hamad, D. & Raman, V. Metabolic syndrome in children and adolescents. Transl. pediatrics 6, 397–407, https://doi.org/10.21037/tp.2017.10.02 (2017). (PMID: 10.21037/tp.2017.10.02)
Ahrens, W. et al. Cohort Profile: The transition from childhood to adolescence in European children–how I.Family extends the IDEFICS cohort. Int. J. Epidemiol. 46, 1394–1395j, https://doi.org/10.1093/ije/dyw317 (2017). (PMID: 10.1093/ije/dyw317280407445837508)
Ahrens, W. et al. The IDEFICS cohort: design, characteristics and participation in the baseline survey. Int. J. Of. Obes. 35, S3, https://doi.org/10.1038/ijo.2011.30 (2011). (PMID: 10.1038/ijo.2011.30)
Ahrens, W. et al. Metabolic syndrome in young children: definitions and results of the IDEFICS study. Int. J. Obes. 38, S4–S14, https://doi.org/10.1038/ijo.2014.130 (2014). (PMID: 10.1038/ijo.2014.130)
Weale, M. E. Quality control for genome-wide association studies. Methods Mol. Biol. 628, 341–372, https://doi.org/10.1007/978-1-60327-367-1_19 (2010). (PMID: 10.1007/978-1-60327-367-1_1920238091)
Ziegler, A. Genome-wide association studies: quality control and population-based measures. Genet. Epidemiol. 33(Suppl 1), S45–S50, https://doi.org/10.1002/gepi.20472 (2009). (PMID: 10.1002/gepi.20472199247162996103)
Aulchenko, Y. S., Ripke, S., Isaacs, A. & van Duijn, C. M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296, https://doi.org/10.1093/bioinformatics/btm108 (2007). (PMID: 10.1093/bioinformatics/btm10817384015)
Zheng, X. et al. A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics 28, 3326–3328, https://doi.org/10.1093/bioinformatics/bts606 (2012). (PMID: 10.1093/bioinformatics/bts606230606153519454)
MacArthur, J. et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic acids Res. 45, D896–D901, https://doi.org/10.1093/nar/gkw1133 (2017). (PMID: 10.1093/nar/gkw113327899670)
Tawfik, N. S. & Spruit, M. R. The SNPcurator: literature mining of enriched SNP-disease associations. Database: J. Biol. databases curation 2018, bay020, https://doi.org/10.1093/database/bay020 (2018). (PMID: 10.1093/database/bay020)
Piñero, J. et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic acids Res. 45, D833–D839, https://doi.org/10.1093/nar/gkw943 (2017). (PMID: 10.1093/nar/gkw94327924018)
Davis, A. P. et al. The Comparative Toxicogenomics Database: update 2019. Nucleic Acids Res, https://doi.org/10.1093/nar/gky868 (2018).
Xu, Z. & Taylor, J. A. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic acids Res. 37, W600–W605, https://doi.org/10.1093/nar/gkp290 (2009). (PMID: 10.1093/nar/gkp290194170632703930)
Wells, G. A. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. (2011).
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 6, e1000097–e1000097, https://doi.org/10.1371/journal.pmed.1000097 (2009). (PMID: 10.1371/journal.pmed.1000097196210722707599)
Chen, H. et al. Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models. Am. J. Hum. Genet. 98, 653–666, https://doi.org/10.1016/j.ajhg.2016.02.012 (2016). (PMID: 10.1016/j.ajhg.2016.02.012270184714833218)
Pruim, R. J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337, https://doi.org/10.1093/bioinformatics/btq419 (2010). (PMID: 10.1093/bioinformatics/btq419206342042935401)
Consortium, G. T. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585, https://doi.org/10.1038/ng.2653 (2013). (PMID: 10.1038/ng.2653)
Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315, https://doi.org/10.1038/ng.2892 (2014). (PMID: 10.1038/ng.2892244872763992975)
Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797, https://doi.org/10.1101/gr.137323.112 (2012). (PMID: 10.1101/gr.137323.112229559893431494)
Graffelman, J. Exploring Diallelic Genetic Markers: The HardyWeinberg Package. Journal of Statistical Software 064 (2015).
Higgins, J. P. T., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. BMJ 327, 557–560, https://doi.org/10.1136/bmj.327.7414.557 (2003). (PMID: 10.1136/bmj.327.7414.55712958120192859)
Peters, J. L., Sutton, A. J., Jones, D. R., Abrams, K. R. & Rushton, L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J. Clin. Epidemiol. 61, 991–996, https://doi.org/10.1016/j.jclinepi.2007.11.010 (2008). (PMID: 10.1016/j.jclinepi.2007.11.01018538991)
Egger, M., Smith, G. D., Schneider, M. & Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 315, 629–634, https://doi.org/10.1136/bmj.315.7109.629 (1997). (PMID: 10.1136/bmj.315.7109.62921274532127453)
Ahmad, T. et al. The fat-mass and obesity-associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am. Heart J. 160, 1163–1169, https://doi.org/10.1016/j.ahj.2010.08.002 (2010). (PMID: 10.1016/j.ahj.2010.08.002211466733058560)
Armamento-Villareal, R. et al. The FTO gene is associated with a paradoxically favorable cardiometabolic risk profile in frail, obese older adults. Pharmacogenet Genomics 26, 154–160, https://doi.org/10.1097/FPC.0000000000000201 (2016). (PMID: 10.1097/FPC.0000000000000201267099114919233)
Attaoua, R. et al. 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. 35, 476–483, https://doi.org/10.1016/j.diabet.2009.07.002 (2009). (PMID: 10.1016/j.diabet.2009.07.00219818665)
Attaoua, R. et al. FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochemical Biophysical Res. Commun. 373, 230–234, https://doi.org/10.1016/j.bbrc.2008.06.039 (2008). (PMID: 10.1016/j.bbrc.2008.06.039)
Baik, I. & Shin, C. Interactions between the FTO rs9939609 polymorphism, body mass index, and lifestyle-related factors on metabolic syndrome risk. Nutr 6, 78–85, https://doi.org/10.4162/nrp.2012.6.1.78 (2012). (PMID: 10.4162/nrp.2012.6.1.78)
Chedraui, P. et al. Polymorphisms of the FTO and MTHFR genes and vascular, inflammatory and metabolic marker levels in postmenopausal women. J. Endocrinol. Invest. 39, 885–890, https://doi.org/10.1007/s40618-016-0443-7 (2016). (PMID: 10.1007/s40618-016-0443-726902996)
Col, N., Demircioglu-Kilic, B., Nacak, M. & Araz, M. Adolescent obesity and the role of the fat mass and obesity-associated gene polymorphism. Clin. Invest. Med. 40, E235–E242, https://doi.org/10.25011/cim.v40i6.29124 (2017). (PMID: 10.25011/cim.v40i6.2912429256389)
de Luis, D. A. et al. Relation of the rs9939609 gene variant in FTO with metabolic syndrome in obese female patients. J. Diabetes Complications 27, 346–350, https://doi.org/10.1016/j.jdiacomp.2013.02.003 (2013). (PMID: 10.1016/j.jdiacomp.2013.02.00323490278)
Dusatkova, L. et al. Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents. Folia Biol. 59, 123–133 (2013).
Elouej, S. et al. Association of genetic variants in the FTO gene with metabolic syndrome: A case-control study in the Tunisian population. J. Diabetes Complications 30, 206–211, https://doi.org/10.1016/j.jdiacomp.2015.11.013 (2016). (PMID: 10.1016/j.jdiacomp.2015.11.01326700404)
Fawwad, A., Siddiqui, I. A., Zeeshan, N. F., Shahid, S. M. & Basit, A. Association of SNP rs9939609 in FTO gene with metabolic syndrome in type 2 diabetic subjects, rectruited from a tertiary care unit of Karachi, Pakistan. Pak 31, 140–145, https://doi.org/10.12669/pjms.311.6524 (2015). (PMID: 10.12669/pjms.311.6524)
Freathy, R. M. et al. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes 57, 1419–1426, https://doi.org/10.2337/db07-1466 (2008). (PMID: 10.2337/db07-1466183469833073395)
Hotta, K. et al. Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population. J. Hum. Genet. 56, 647–651, https://doi.org/10.1038/jhg.2011.74 (2011). (PMID: 10.1038/jhg.2011.7421796137)
Liem, E. T. et al. Influence of common variants near INSIG2, in FTO, and near MC4R genes on overweight and the metabolic profile in adolescence: the TRAILS (TRacking Adolescents’ Individual Lives Survey) Study. Am. J. Clin. Nutr. 91, 321–328, https://doi.org/10.3945/ajcn.2009.28186 (2010). (PMID: 10.3945/ajcn.2009.2818620007308)
Liguori, R. et al. The FTO gene polymorphism (rs9939609) is associated with metabolic syndrome in morbidly obese subjects from southern Italy. Mol. Cell Probes 28, 195–199, https://doi.org/10.1016/j.mcp.2014.03.004 (2014). (PMID: 10.1016/j.mcp.2014.03.00424675148)
Malgorzata, S. et al. Searching for Factors Raising the Incidence of Metabolic Syndrome Among 45-60-Year-Old Women. Aging dis. 9, 831–842, https://doi.org/10.14336/AD.2017.1027 (2018). (PMID: 10.14336/AD.2017.1027302716606147583)
Petkeviciene, J. et al. Physical activity, but not dietary intake, attenuates the effect of the FTO rs9939609 polymorphism on obesity and metabolic syndrome in Lithuanian adult population. Public. Health 135, 23–29, https://doi.org/10.1016/j.puhe.2016.02.009 (2016). (PMID: 10.1016/j.puhe.2016.02.00927003669)
Phillips, C. M. et al. High dietary saturated fat intake accentuates obesity risk associated with the fat mass and obesity-associated gene in adults. J. Nutr. 142, 824–831, https://doi.org/10.3945/jn.111.153460 (2012). (PMID: 10.3945/jn.111.15346022457394)
Ramos, R. B. & Spritzer, P. M. FTO gene variants are not associated with polycystic ovary syndrome in women from Southern Brazil. Gene 560, 25–29, https://doi.org/10.1016/j.gene.2015.01.012 (2015). (PMID: 10.1016/j.gene.2015.01.01225592819)
Ranjith, N., Pegoraro, R. J. & Shanmugam, R. Obesity-associated genetic variants in young Asian Indians with the metabolic syndrome and myocardial infarction. Cardiovasc. J. Afr. 22, 25–30, https://doi.org/10.5830/cvja-2010-036 (2011). (PMID: 10.5830/cvja-2010-036212982023736384)
Reynolds, G. P. et al. The obesity risk gene FTO influences body mass in chronic schizophrenia but not initial antipsychotic drug-induced weight gain in first-episode patients. Int. J. Neuropsychopharmacol. 16, 1421–1425, https://doi.org/10.1017/S1461145712001435 (2013). (PMID: 10.1017/S146114571200143523236985)
Rodrigues, G. K. et al. A single FTO gene variant rs9939609 is associated with body weight evolution in a multiethnic extremely obese population that underwent bariatric surgery. Nutrition 31, 1344–1350, https://doi.org/10.1016/j.nut.2015.05.020 (2015). (PMID: 10.1016/j.nut.2015.05.02026429653)
Sedaghati-Khayat, B. et al. Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS). Eat. Weight. Disorders: EWD 10, 10, https://doi.org/10.1007/s40519-018-0493-2 (2018). (PMID: 10.1007/s40519-018-0493-2)
Sikhayeva, N. et al. Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study. BMC Med. Genet. 18, 76, https://doi.org/10.1186/s12881-017-0443-2 (2017). (PMID: 10.1186/s12881-017-0443-2287387935525290)
Sjogren, M. et al. The search for putative unifying genetic factors for components of the metabolic syndrome. Diabetologia 51, 2242–2251, https://doi.org/10.1007/s00125-008-1151-4 (2008). (PMID: 10.1007/s00125-008-1151-418853134)
Slezak, R., Leszczynski, P., Warzecha, M., Laczmanski, L. & Misiak, B. Assessment of the FTO gene polymorphisms in male patients with metabolic syndrome. Adv 27, 1581–1585, https://doi.org/10.17219/acem/75676 (2018). (PMID: 10.17219/acem/75676)
Steemburgo, T. et al. The rs7204609 polymorphism in the fat mass and obesity-associated gene is positively associated with central obesity and microalbuminuria in patients with type 2 diabetes from Southern Brazil. J. Ren. Nutr. 22, 228–236, https://doi.org/10.1053/j.jrn.2011.03.004 (2012). (PMID: 10.1053/j.jrn.2011.03.00421741858)
Tabara, Y. et al. Prognostic significance of FTO genotype in the development of obesity in Japanese: the J-SHIPP study. Int. J. Obes. 33, 1243–1248, https://doi.org/10.1038/ijo.2009.161 (2009). (PMID: 10.1038/ijo.2009.161)
Vankova, D., Radanova, M., Kiselova-Kaneva, Y., Madjova, V. & Ivanova, D. The fto rs9939609, adipoq rs1501299, rs822391, and adipor2 rs16928662 polymorphisms relationship to obesity and metabolic syndrome in bulgarian sample. Biotechnol. Biotechnol. Equip. 26, 65–71, https://doi.org/10.5504/50yrtimb.2011.0012 (2012). (PMID: 10.5504/50yrtimb.2011.0012)
Wang, T. et al. The association between common genetic variation in the FTO gene and metabolic syndrome in Han Chinese. Chin. Med. J. 123, 1852–1858 (2010). (PMID: 20819567)
Zhao, X. et al. An obesity genetic risk score is associated with metabolic syndrome in Chinese children. Gene 535, 299–302, https://doi.org/10.1016/j.gene.2013.11.006 (2014). (PMID: 10.1016/j.gene.2013.11.00624269186)
Al-Attar, S. A. et al. Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample. Cardiovascular Diabetology 7, https://doi.org/10.1186/1475-2840-7-5 (2008).
Cheung, C. Y. et al. Genetic variants associated with persistent central obesity and the metabolic syndrome in a 12-year longitudinal study. Eur. J. Endocrinol. 164, 381–388, https://doi.org/10.1530/EJE-10-0902 (2011). (PMID: 10.1530/EJE-10-090221147891)
Cruz, M. et al. Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City. Diabetes Metab. Res. Rev. 26, 261–270, https://doi.org/10.1002/dmrr.1082 (2010). (PMID: 10.1002/dmrr.108220503258)
Elouej, S. et al. Association of rs9939609 Polymorphism with Metabolic Parameters and FTO Risk Haplotype Among Tunisian Metabolic Syndrome. Metab. Syndr. Relat. Disord. 14, 121–128, https://doi.org/10.1089/met.2015.0090 (2016). (PMID: 10.1089/met.2015.009026741700)
Guclu-Geyik, F. et al. Risk of obesity and metabolic syndrome associated with FTO gene variants discloses clinically relevant gender difference among Turks. Mol. Biol. Rep. 43, 485–494, https://doi.org/10.1007/s11033-016-3992-0 (2016). (PMID: 10.1007/s11033-016-3992-027146691)
Hu, Y. H. et al. Association between polymorphisms of fat mass and obesity-associated gene and metabolic syndrome in Kazakh adults of Xinjiang, China. Genet. Mol. Res. 14, 14597–14606, https://doi.org/10.4238/2015.November.18.23 (2015). (PMID: 10.4238/2015.November.18.2326600519)
Khella, M. S., Hamdy, N. M., Amin, A. I. & El-Mesallamy, H. O. The (FTO) gene polymorphism is associated with metabolic syndrome risk in Egyptian females: a case- control study. BMC Med. Genet. 18, 101, https://doi.org/10.1186/s12881-017-0461-0 (2017). (PMID: 10.1186/s12881-017-0461-0289158595603034)
Rotter, I. et al. Relationships between FTO rs9939609, MC4R rs17782313, and PPARgamma rs1801282 polymorphisms and the occurrence of selected metabolic and hormonal disorders in middle-aged and elderly men - a preliminary study. Clin. Interv. Aging 11, 1723–1732, https://doi.org/10.2147/CIA.S120253 (2016). (PMID: 10.2147/CIA.S120253279205115126003)
Hasan, H. A., AbuOdeh, R. O., Muda, W., Mohamed, H. & Samsudin, A. R. Association of Vitamin D receptor gene polymorphisms with metabolic syndrome and its components among adult Arabs from the United Arab Emirates. Diabetes Metab. Syndr. 11(Suppl 2), S531–S537, https://doi.org/10.1016/j.dsx.2017.03.047 (2017). (PMID: 10.1016/j.dsx.2017.03.04728392355)
Larder, R., Cheung, M. K., Tung, Y. C., Yeo, G. S. & Coll, A. P. Where to go with FTO? Trends Endocrinol. metabolism: TEM. 22, 53–59, https://doi.org/10.1016/j.tem.2010.11.001 (2011). (PMID: 10.1016/j.tem.2010.11.00121131211)
Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472, https://doi.org/10.1126/science.1151710 (2007). (PMID: 10.1126/science.1151710179918262668859)
Javierre, B. M. et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 20, 170–179, https://doi.org/10.1101/gr.100289.109 (2010). (PMID: 10.1101/gr.100289.109200286982813473)
Campión, J., Milagro, F. I. & Martínez, J. A. Individuality and epigenetics in obesity. Obes. Rev. 10, 383–392, https://doi.org/10.1111/j.1467-789X.2009.00595.x (2009). (PMID: 10.1111/j.1467-789X.2009.00595.x19413700)
Mizuno, T. M. Fat Mass and Obesity Associated (FTO) Gene and Hepatic Glucose and Lipid Metabolism. Nutrients 10, 1600, https://doi.org/10.3390/nu10111600 (2018). (PMID: 10.3390/nu101116006266206)
Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375, https://doi.org/10.1038/nature13138 (2014). (PMID: 10.1038/nature13138246469994113484)
Zou, Y. et al. IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk. EBioMedicine 24, 64–75, https://doi.org/10.1016/j.ebiom.2017.09.010 (2017). (PMID: 10.1016/j.ebiom.2017.09.010289889795652024)
Basile, K. J., Johnson, M. E., Xia, Q. & Grant, S. F. A. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int. J. Endocrinol. 2014, 769671–769671, https://doi.org/10.1155/2014/769671 (2014). (PMID: 10.1155/2014/769671247196153955626)
Kilpelainen, T. O. et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat. Genet. 43, 753–760, https://doi.org/10.1038/ng.866 (2011). (PMID: 10.1038/ng.866217060033262230)
Wang, Q. et al. Relationship between fat mass and obesity-associated gene expression and type 2 diabetes mellitus severity. Exp. Ther. Med. 15, 2917–2921, https://doi.org/10.3892/etm.2018.5752 (2018). (PMID: 10.3892/etm.2018.5752294566975795504)
Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894, https://doi.org/10.1126/science.1141634 (2007). (PMID: 10.1126/science.1141634174348692646098)
Lauria, F. et al. Prospective analysis of the association of a common variant of FTO (rs9939609) with adiposity in children: results of the IDEFICS study. PLoS one 7, e48876–e48876, https://doi.org/10.1371/journal.pone.0048876 (2012). (PMID: 10.1371/journal.pone.0048876231554223498350)
Hertel, J. K. 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 60, 1637–1644, https://doi.org/10.2337/db10-1340 (2011). (PMID: 10.2337/db10-1340213985253292341)
Zabena, C. et al. The FTO obesity gene. Genotyping and gene expression analysis in morbidly obese patients. Obes. Surg. 19, 87–95, https://doi.org/10.1007/s11695-008-9727-0 (2009). (PMID: 10.1007/s11695-008-9727-018855084)
Al-Attar, S. A. et al. Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample. Cardiovasc. Diabetol. 7, 5, https://doi.org/10.1186/1475-2840-7-5 (2008). (PMID: 10.1186/1475-2840-7-5183392042275229)
Povel, C. M., Boer, J. M., Reiling, E. & Feskens, E. J. Genetic variants and the metabolic syndrome: a systematic review. Obes. Rev. 12, 952–967, https://doi.org/10.1111/j.1467-789X.2011.00907.x (2011). (PMID: 10.1111/j.1467-789X.2011.00907.x21749608)
Frisdal, E. et al. Functional interaction between −629C/A, −971G/A and −1337C/T polymorphisms in the CETP gene is a major determinant of promoter activity and plasma CETP concentration in the REGRESS Study. Hum. Mol. Genet. 14, 2607–2618, https://doi.org/10.1093/hmg/ddi291 (2005). (PMID: 10.1093/hmg/ddi29116049032)
Lu, H. et al. Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism. J. Mol. Med. 81, 246–255, https://doi.org/10.1007/s00109-002-0414-7 (2003). (PMID: 10.1007/s00109-002-0414-712700892)
Boekholdt, S. M. et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation 111, 278–287, https://doi.org/10.1161/01.Cir.0000153341.46271.40 (2005). (PMID: 10.1161/01.Cir.0000153341.46271.4015655129)
O’Neill, S. & O’Driscoll, L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes. Rev. 16, 1–12, https://doi.org/10.1111/obr.12229 (2015). (PMID: 10.1111/obr.1222925407540)
Heindel, J. J. et al. Metabolism disrupting chemicals and metabolic disorders. Reprod. Toxicol. 68, 3–33, https://doi.org/10.1016/j.reprotox.2016.10.001 (2017). (PMID: 10.1016/j.reprotox.2016.10.00127760374)
Wang, H., Dong, S., Xu, H., Qian, J. & Yang, J. Genetic variants in FTO associated with metabolic syndrome: a meta- and gene-based analysis. Mol. Biol. Rep. 39, 5691–5698, https://doi.org/10.1007/s11033-011-1377-y (2012). (PMID: 10.1007/s11033-011-1377-y22189543)
Fall, T. et al. The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. PLoS Medicine/Public Library Sci. 10, e1001474, https://doi.org/10.1371/journal.pmed.1001474 (2013). (PMID: 10.1371/journal.pmed.1001474)
Zhou, D. et al. Common variant (rs9939609) in the FTO gene is associated with metabolic syndrome. Mol. Biol. Rep. 39, 6555–6561, https://doi.org/10.1007/s11033-012-1484-4 (2012). (PMID: 10.1007/s11033-012-1484-422311015)
Qi, L. et al. Fat mass-and obesity-associated (FTO) gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test. Diabetes 57, 3145–3151, https://doi.org/10.2337/db08-0006 (2008). (PMID: 10.2337/db08-0006186479532570413)
Kelishadi, R., Hovsepian, S. & Javanmard, S. H. A Systematic review of single nucleotide polymorphisms associated with metabolic syndrome in children and adolescents. children 29, 46 (2017).
Kraft, P., Zeggini, E. & Ioannidis, J. P. A. Replication in genome-wide association studies. Stat. Sci. 24, 561–573, https://doi.org/10.1214/09-STS290 (2009). (PMID: 10.1214/09-STS290204545412865141)
Graff, M. et al. BMI loci and longitudinal BMI from adolescence to young adulthood in an ethnically diverse cohort. Int. J. Obes. 41(2005), 759–768, https://doi.org/10.1038/ijo.2016.233 (2017). (PMID: 10.1038/ijo.2016.233)
Hardy, R. et al. Life course variations in the associations between FTO and MC4R gene variants and body size. Hum. Mol. Genet. 19, 545–552, https://doi.org/10.1093/hmg/ddp504 (2010). (PMID: 10.1093/hmg/ddp50419880856)

0 (CETP protein, human)
0 (Cholesterol Ester Transfer Proteins)
EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
EC 1.14.11.33 (FTO protein, human)

Date Created: 20200430 Date Completed: 20201125 Latest Revision: 20210428

20250114

PMC7188794

10.1038/s41598-020-64031-2

32346024