TCF7L2 Polymorphism rs7903146 and Predisposition for Type 2 Diabetes Mellitus in Obese Children

Abstract

Polymorphism rs7903146 in transcription factor 7-like2 gene (TCF7L2) is associated with type 2-diabetes mellitus (T2DM) in adults. Concerned with predisposition for diabetes mellitus in obese children, we tested if risk genotypes TC and TT of rs7903146 are more common in obese children with increased homeostasis model assessment insulin resistance index (HOMA-IR) compared to obese controls with normal HOMA-IR. As exploratory analysis, we also calculated beta-cell function for these risk genotypes and measured glucagon-like peptide 1 (GLP-1) in a subgroup. The cohort was 401 obese children (BMI > 2SDS; 211 female; 59% presenting increased HOMA-IR) from two German outpatient obesity referral centers. Genotype distributions in patients presenting increased HOMA-IR (TT: 10.18%, CT: 35.65%, CC: 54.17%) and in patients with normal HOMA-IR (TT: 8.66%, CT: 42.67%, CC: 48.67%) provided no significant effect of these two risk genotypes (p > 0.2). Correction for possible confounder's gender, age, pubertal stage, and BMI revealed no association with glucose metabolism parameters including GLP-1. However, exploratory HOMA-B% index was comparatively higher in TT-homozygotes (p=0.021) as compared to CC-homozygotes. We conclude that even though TT and CT genotypes were not higher in patients presenting elevated HOMA-IR, the higher HOMA-B% index in TT-homozygotes indicates TCF7L2 to be a susceptibility gene for the development of impaired glucose tolerance in obese children as demonstrated in several adult cohort studies.

Key words

childhood obesity - insulin resistance - diabetes mellitus

References

• 1 Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S. Obesity and the metabolic syndrome in children and adolescents.  N Engl J Med. 2004;  350 2362-2374
• 2 Wiegand S, Maikowski U, Blankenstein O, Biebermann H, Tarnow P, Gruters A. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity – a problem that is no longer restricted to minority groups.  Eur J Endocrinol. 2004;  151 199-206
• 3 Reinehr T. Clinical presentation of type 2 diabetes mellitus in children and adolescents.  Int J Obes (Lond). 2005;  29 ((Suppl 2)) 105-110
• 4 Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.  Nat Genet. 2006;  38 320-323
• 5 Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, Frayling TM, Yajnik CS. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.  Diabetologia. 2007;  50 63-67
• 6 Cauchi S, Meyre D, Choquet H, Dina C, Born C, Marre M, Balkau B, Froguel P. DESIR Study Group . TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study.  Diabetes. 2006;  55 3189-3192
• 7 Damcott CM, Pollin TI, Reinhart LJ, Ott SH, Shen H, Silver KD, Mitchell BD, Shuldiner AR. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.  Diabetes. 2006;  55 2654-2659
• 8 Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, Li KW, Palmen J, Miller MA, Cappuccio FP, Elkeles R, Godsland I, Miller GJ, Talmud PJ. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.  J Mol Med. 2006;  84 1-10
• 9 Scott LJ, Bonnycastle LL, Willer CJ, Sprau AG, Jackson AU, Narisu N, Duren WL, Chines PS, Stringham HM, Erdos MR, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Collins FS, Boehnke M. Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample.  Diabetes. 2006;  55 2649-2653
• 10 Weedon MN, MacCarthy MI, Hitman G, Walker M, Groves CJ, Zeggini E, Rayner NW, Shields B, Owen KR, Hattersley AT, Frayling TM. Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.  PLoS Med. 2006;  3 e374
• 11 Lehman DM, Hunt KJ, Leach RJ, Hamlington J, Arya R, Abboud HE, Duggirala R, Blangero J, Goring HH, Stern MP. Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans.  Diabetes. 2007;  56 389-393
• 12 Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, Buchanan TA. Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes and interacts with adiposity to alter insulin secretion in mexican americans.  Diabetes. 2007;  56 1481-1485
• 13 Florez JC, Jablonski KA, Bayley N, Pollin TI, Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D. Diabetes Prevention Program Research Group . TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program.  N Engl J Med. 2006;  355 241-250
• 14 American Diabetes Association . Type 2 diabetes in children and adolescents.  Pediatrics. 2000;  105 671-680
• 15 Hebebrand J, Himmelmann GW, Heseker H, Schäfer H, Remschmidt H. Use of percentiles for the body mass index in anorexia nervosa: diagnostic, epidemiological and therapeutic considerations.  Int J Eat Disord. 1996;  19 359-369
• 16 Allard P, Delvin EE, Paradis G, Hanley JA, O’Loughlin J, Lavallee C, Levy E, Lambert M. Distribution of fasting plasma insulin, free fatty acids, and glucose concentrations and of homeostasis model assessment of insulin resistance in a representative sample of Quebec children and adolescents.  Clin Chem. 2003;  49 644-649
• 17 Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ, Yanovski JA. Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children.  Diab Care. 2001;  25 2081-2087
• 18 Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms.  Nucleic Acids Res. 2001;  29 E88
• 19 Helgason A, Palsson S, Thorleifsson G, Grant SF, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, Benediktsson R, Hinney A, Hansen T, Andersen G, Borch-Johnsen K, Jorgensen T, Schafer H, Faruque M, Doumatey A, Zhou J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Sigurdsson G, Hebebrand J, Pedersen O, Thorsteinsdottir U, Gulcher JR, Kong A, Rotimi C, Stefansson K. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.  Nat Genet. 39;  2007 218-225
• 20 Körner A, Berndt J, Sturmvoll M, Kiess W, Kovacs P. TCF7L2-gene polymorphisms confer an increased risk for early impairment of glucose metabolism and increased height in obese children.  J Clin Endocrin Metab. 2007;  92 1956-1960
• 21 Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.  J Clin Invest. 2007;  117 2155-2121
• 22 Marzi C, Huth C, Kolz M, Grallert H, Meisinger C, Wichmann HE, Rathmann W, Herder C, Illig T. Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys.  Horm Metab Res. 2007;  39 46-52
• 23 Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta.  J Biol Chem. 2005;  280 1457-1464
• 24 Schäfer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, T’hart LM, Nijpels G, Haeften TW van, Häring HU, Fritsche A. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms.  Diabetologia. 2007;  50 2443-2450

Support: This work was supported by grants from the Bonfor Research Foundation, University of Bonn, Germany and the German Ministry of Education and Research (Bundesministerium für Bildung und Forschung; National Genome Net, NGFN 1 and 2.

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