TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study
Open Access
- 31 January 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Diabetologia
- Vol. 52 (4), 614-620
- https://doi.org/10.1007/s00125-009-1266-2
Abstract
Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10−7) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls.This publication has 19 references indexed in Scilit:
- A 100K Genome-Wide Association Scan for Diabetes and Related Traits in the Framingham Heart StudyDiabetes, 2007
- Visceral and Subcutaneous Adipose Tissue Volumes Are Cross-Sectionally Related to Markers of Inflammation and Oxidative StressCirculation, 2007
- Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetesJCI Insight, 2007
- TCF7L2 Polymorphisms Modulate Proinsulin Levels and β-Cell Function in a British Europid PopulationDiabetes, 2007
- Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolutionNature Genetics, 2007
- TCF7L2 Variation Predicts Hyperglycemia Incidence in a French General PopulationDiabetes, 2006
- TCF7L2Polymorphisms and Progression to Diabetes in the Diabetes Prevention ProgramThe New England Journal of Medicine, 2006
- Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetesNature Genetics, 2006
- Management of Dyslipidemia in Children and Adolescents With DiabetesDiabetes Care, 2003
- Report of the Expert Committee on the Diagnosis and Classification of Diabetes MellitusDiabetes Care, 2003