Abstract
BackgroundGenetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.MethodsWe genotyped the single nucleotide polymorphisms (SNP) rs7903146 of the TCF7L2 gene in 560 patients with known coronary disease enrolled in the MASS II (Medicine, Angioplasty, or Surgery Study) Trial and in 1,449 residents of Vitoria, in Southeast Brazil. The associations of this gene variant to diabetes risk and metabolic characteristics in these two different populations were analyzed. To access the potential benefit of using this marker for diabetes risk prediction in the general population we analyzed the impact of this genetic variant on a validated diabetes risk prediction tool based on clinical characteristics developed for the Brazilian general population.ResultsSNP rs7903146 of the TCF7L2 gene was significantly associated with type 2 diabetes in the MASS-II population (OR = 1.57 per T allele, p = 0.0032), confirming, in the Brazilian population, previous reports of the literature. Addition of this polymorphism to an established clinical risk prediction score did not increased model accuracy (both area under ROC curve equal to 0.776).ConclusionTCF7L2 rs7903146 T allele is associated with a 1.57 increased risk for type 2 diabetes in a Brazilian cohort of patients with known coronary heart disease. However, the inclusion of this polymorphism in a risk prediction tool developed for the general population resulted in no improvement of performance. This is the first study, to our knowledge, that has confirmed this recent association in a South American population and adds to the great consistency of this finding in studies around the world. Finally, confirming the biological association of a genetic marker does not guarantee improvement on already established screening tools based solely on demographic variables.
Highlights
Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide
In the MASS-II population, a total of 560 individuals were genotyped for TCF7L2 gene variant rs7903146 and the genotypic distribution for this variant was in Hardy-Weinberg equilibrium
After adjusting for other covariates potentially associated with Type 2 diabetes mellitus (T2D) risk, presence of allele T was still significantly associated with a 1.61 (95%CI 1.18–2.19) increased risk of presenting T2D (p = 0.0025) (Table 4)
Summary
Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. Two additional cohorts showed similar associations, giving a combined odds ratio (OR) of 1.6 (95% confidence interval (CI) 1.4 to 1.7, p = 4.7 × 10-18 per allele) This finding has readily been replicated in cohorts of European [1,2,3,4,5,6,7,8,9,10,11,12,13], Asian [6,14,15,16] and African [6,17] descent, showing very similar results. There are much fewer studies that analyzed the effect of this polymorphism in the general population [10,18], but they suggest that diabetic carriers of the at-risk allele have more severe β-cell dysfunction and more microvascular complications but less metabolic syndrome features and a more protective lipid profile than non-carriers
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