Loci of TCF7L2, HHEX and IDE on Chromosome 10q and the Susceptibility of their Genetic Polymorphisms to Type 2 Diabetes

Abstract

TCF7L2, HHEX and IDE on chromosome 10q23-25 reside within the linkage region for type 2 diabetes (T2D). Previous studies including ours have demonstrated that genetic polymorphisms in these three loci are associated with T2D, respectively. But, it is unclear whether TCF7L2, independently or interactively with HHEX and IDE, confer the susceptibility to T2D. In the present study, we first replicated genetic association study of the TCF7L2 gene in a Swedish cohort including 528 non-diabetic healthy controls and 243 T2D patients and then evaluated combining effect from common risk polymorphisms in TCF7L2-HHEX-IDE loci. T2D patients were diagnosed in the intermediate study time. To avoid influence from anti-diabetic treatment, baseline data in all T2D patients were used for analysis. We found that SNPs rs7901695, rs4506565, rs7903146 and rs12255372 in the TCF7L2 gene were strongly associated with T2D (p<0.004). In rs7903146, T2D patients carrying genotypes CT or TT had higher fasting plasma glucose (FPG) levels (p=0.042) and lower HOMA-β index (p=0.015) and BMI (p=0.015) compared to the patients carrying CC genotype. Furthermore, the risk alleles from TCF7L2 rs7903146 polymorphism either with IDE rs2251101 polymorphism (p=0.0257, OR=1.398) or with HHEX rs1544210 polymorphism (p=0.0024, OR=1.514) were significantly associated with T2D. When risk alleles from three loci were combined, the association with T2D remained significant (p=0.0018, OR=1.506). The present study thus provides evidence that TCF7L2, as the main gene, together with HHEX and IDE loci have combining effects on genetic predisposition to T2D.

Key words

type 2 diabetes - TCF7L2 - IDE - HHEX

References

• 1 Reynisdottir I, Thorleifsson G, Benediktsson R. et al . Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2.  Am J Hum Genet. 2003;  73 323-335
• 2 Wiltshire S, Hattersley AT, Hitman GA. et al . A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.  Am J Hum Genet. 2001;  69 553-569
• 3 Watanabe RM, Ghosh S, Langefeld CD. et al . The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes.  Am J Hum Genet. 2000;  67 1174-1185
• 4 Duggirala R, Blangero J, Almasy L. et al . Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.  Am J Hum Genet. 1999;  64 1127-1140
• 5 Ehm MG, Karnoub MC, Sakul H. et al. . Genetics of NIDDM. Genomewide search for type 2 diabetes susceptibility genes in four American populations.  Am J Hum Genet. 2000;  66 1871-1881
• 6 Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential.  Endocr Rev. 1998;  19 608-624
• 7 Fakhrai-Rad H, Nikoshkov A, Kamel A. et al . Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.  Hum Mol Genet. 2000;  9 2149-2158
• 8 Karamohamed S, Demissie S, Volcjak J. et al. . Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study.  Diabetes. 2003;  52 1562-1567
• 9 Gu HF, Efendic S, Nordman S. et al . Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels.  Diabetes. 2004;  53 2137-2142
• 10 Furukawa Y, Shimada T, Furuta H. et al . Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population.  J Clin Endocrinol Metab. 2008;  93 310-314
• 11 Schulze MB, Al-Hasani H, Boeing H. et al . Variation in the HHEX-IDE gene region predisposes to type 2 diabetes in the prospective, population-based EPIC-Potsdam cohort.  Diabetologia. 2007;  50 2405-2407
• 12 Sladek R, Rocheleau G, Rung J. et al . A genome-wide association study identifies novel risk loci for type 2 diabetes.  Nature. 2007;  445 881-885
• 13 Horikoshi M, Hara K, Ito C. et al . Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population.  Diabetologia. 2007;  50 2461-2466
• 14 Zeggini E, Weedon MN, Lindgren CM. et al. . Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.  Science. 2007;  316 1336-1341
• 15 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
• 16 Grant SF, Thorleifsson G, Reynisdottir I. et al . Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.  Nat Genet. 2006;  38 320-323
• 17 Buchbinder S, Rudofsky Jr G, Humpert PM. et al . The DG10S478 variant in the TCF7L2 gene is not associated with microvascular complications in type 2 diabetes.  Exp Clin Endocrinol Diabetes. 2008;  116 211-214
• 18 Weedon MN. The importance of TCF7L2.  Diabet Med. 2007;  24 1062-1066
• 19 Elbein SC. Evaluation of polymorphisms known to contribute to risk for diabetes in Aferican and African-American populations.  Curr Opin Clin Nutr Metab Care. 2007;  10 415-419
• 20 Florez JC. The new type 2 diabetes gene TCF7L2.  Curr Opin Clin Nutr Metab Care. 2007;  10 391-396
• 21 Frayling TM. A new era in finding type 2 diabetes gene – the unusual suspects.  Diabet Med. 2007;  24 696-701
• 22 Owen KR, MacCarthy MI. Genetics of type 2 diabetes.  Curr Opin Clin Nutr Metab Care. 2007;  17 239-244
• 23 Lyssenko V, Lupi R, Marchetti P. et al . Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.  J Clin Invest. 2007;  117 2155-2163
• 24 Carlsson S, Persson PG, Alvarsson M. et al . Weight history, glucose intolerance, and insulin levels in middle-aged Swedish men.  Am J Epidemiol. 1998;  148 539-545
• 25 Wang J, Kuusisto J, Vänttinen M. et al . Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion.  Diabetologia. 2007;  50 1192-1200
• 26 Elbein SC, Chu WS, Das SK. et al . Transcription factor 7-like 2 polymorphisms and type 2 diabetes, glucose homeostasis traits and gene expression in US participants of European and African descent.  Diabetologia. 2007;  50 1621-1630
• 27 Nordman S. Identification of susceptibility genes in type 2 diabetes.  ISBN 978-91-7375-492-1. 200;  1-46
• 28 Weedon MN, MacCarthy MI, Hitman G. et al . Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.  PLoS Med. 2006;  3 1877-1882
• 29 Cauchi S, Meyre D, Dina C. et al . Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.  Diabetes. 2006;  55 2903-2908
• 30 Humphries SE, Gable D, Cooper JA. et al . 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 1005-1014
• 31 Schäfer SA, Tschritter O, Machicao F. et al . Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms.  Diabetologia. 2007;  50 2443-2450
• 32 Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation.  J Bio Chem. 2008;  283 8723-8735

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