Association of Variants of the TCF7L2 Gene with Increases in the Risk of Type 2 Diabetes and the Proinsulin:insulin Ratio in the Spanish Population

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2008 Aug 21

PMID 18712344

Citations 20

Authors

J L Gonzalez-Sanchez

M T Martinez-Larrad

C Zabena

M Perez-Barba

M Serrano-Rios

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: The gene encoding transcription factor 7-like 2 (TCF7L2) has been related to type 2 diabetes in multiple ethnic groups. Here, we investigate whether three single nucleotide polymorphisms (SNPs) in the TCF7L2 gene are associated with an impaired proinsulin:insulin ratio.

Methods: In this study we examined the associations between SNPs rs7901695, rs7903146 and rs12255372 in the TCF7L2 gene and metabolic variables affecting type 2 diabetes in a population-based study of 706 unrelated individuals (47% men and 53% women; aged 35-74 years) from the province of Segovia in central Spain (Castille), including 180 individuals with type 2 diabetes.

Results: The minor allele frequency of rs7901695, rs7903146 and rs12255372 was significantly higher in diabetic patients compared with that in non-diabetic individuals. The T (minor) allele of the variant rs7903146 was significantly associated with a greater OR for type 2 diabetes adjusted for age, sex and BMI in logistic regression analysis: OR 1.29 (95% CI 1.06-1.57, p = 0.01). This risk allele was also associated with an increased proinsulin:insulin ratio after OGTT. Similar results were obtained for the other TCF7L2 SNPs.

Conclusions/interpretation: Our results provide further evidence supporting the belief that the TCF7L2 gene is a major determinant of type 2 diabetes risk in Spain, as in other southern European populations. The association with increased proinsulin:insulin ratio after an OGTT suggests that TCF7L2 might be involved in insulin synthesis and processing.

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References

Roder M, Porte Jr D, Schwartz R, Kahn S . Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1998; 83(2):604-8. DOI: 10.1210/jcem.83.2.4544. View

Helgason A, Palsson S, Thorleifsson G, Grant S, Emilsson V, Gunnarsdottir S . Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet. 2007; 39(2):218-25. DOI: 10.1038/ng1960. View

Cauchi S, Choquet H, Gutierrez-Aguilar R, Capel F, Grau K, Proenca C . Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring). 2008; 16(2):476-82. DOI: 10.1038/oby.2007.77. View

Pearson E, Donnelly L, Kimber C, Whitley A, Doney A, McCarthy M . Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes. 2007; 56(8):2178-82. DOI: 10.2337/db07-0440. View

Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P . Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007; 117(8):2155-63. PMC: 1934596. DOI: 10.1172/JCI30706. View

Rulifson I, Karnik S, Heiser P, Ten Berge D, Chen H, Gu X . Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A. 2007; 104(15):6247-52. PMC: 1847455. DOI: 10.1073/pnas.0701509104. View

Cauchi S, Froguel P . TCF7L2 genetic defect and type 2 diabetes. Curr Diab Rep. 2008; 8(2):149-55. DOI: 10.1007/s11892-008-0026-x. View

Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28(7):412-9. DOI: 10.1007/BF00280883. View

Florez J . The new type 2 diabetes gene TCF7L2. Curr Opin Clin Nutr Metab Care. 2007; 10(4):391-6. DOI: 10.1097/MCO.0b013e3281e2c9be. View

10.

Cauchi S, El Achhab Y, Choquet H, Dina C, Krempler F, Weitgasser R . TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med (Berl). 2007; 85(7):777-82. DOI: 10.1007/s00109-007-0203-4. View

11.

Zethelius B, Hales C, Lithell H, Berne C . Insulin resistance, impaired early insulin response, and insulin propeptides as predictors of the development of type 2 diabetes: a population-based, 7-year follow-up study in 70-year-old men. Diabetes Care. 2004; 27(6):1433-8. DOI: 10.2337/diacare.27.6.1433. View

12.

Florez J, Jablonski K, Bayley N, Pollin T, de Bakker P, Shuldiner A . TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006; 355(3):241-50. PMC: 1762036. DOI: 10.1056/NEJMoa062418. View

13.

Schafer S, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B . Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia. 2007; 50(12):2443-50. PMC: 2063563. DOI: 10.1007/s00125-007-0753-6. View

14.

Florez J, Hirschhorn J, Altshuler D . The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genomics Hum Genet. 2003; 4:257-91. DOI: 10.1146/annurev.genom.4.070802.110436. View

15.

Kirchhoff K, Machicao F, Haupt A, Schafer S, Tschritter O, Staiger H . Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia. 2008; 51(4):597-601. DOI: 10.1007/s00125-008-0926-y. View

16.

Loos R, Franks P, Francis R, Barroso I, Gribble F, Savage D . TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. Diabetes. 2007; 56(7):1943-7. PMC: 2668957. DOI: 10.2337/db07-0055. View

17.

Grant S, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J . Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006; 38(3):320-3. DOI: 10.1038/ng1732. View

18.

Saxena R, Gianniny L, Burtt N, Lyssenko V, Giuducci C, Sjogren M . Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes. 2006; 55(10):2890-5. DOI: 10.2337/db06-0381. View