An alternative effector gene at the type 2 diabetes-associated TCF7L2 locus?

Bunt, Martijn van de

doi:10.1007/s00125-016-4103-4

Cited by 7 publications

(3 citation statements)

References 14 publications

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“…The mechanisms that underlie the metabolic abnormalities observed in carriers of the TCF7L2 genetic variants in the current study are unknown. However, TCF7L2 has been reported to play a role in various aspects of glucose metabolism (17–19), including a possible regulatory role of a TCF7L2 variant on ACSL5 expression and thus, potentially, on insulin sensitivity (20,21). Further testing of this hypothesis may be achieved by treating patients with therapies that are relevant to the disease phenotype and genetic background.…”

Section: Discussionmentioning

confidence: 99%

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TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

et al. 2017

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OBJECTIVEThe phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis. RESEARCH DESIGN AND METHODSWe studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders. RESULTSThe rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ‡12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP. CONCLUSIONSIn this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ‡12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms.Although the autoimmune destruction of b-cells has a major role in the development of type 1 diabetes, there is growing evidence that the differences in clinical, metabolic, immunologic, and genetic characteristics among patients (1) likely reflect diverse etiology and pathogenesis (2). Factors that govern this heterogeneity are poorly understood, yet these may have important implications for prognosis, therapy, and prevention.The transcription factor 7 like 2 (TCF7L2) locus contains the single nucleotide polymorphism (SNP) most strongly associated with type 2 diabetes risk, with an ;30%

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Section: Discussionmentioning

confidence: 99%

“…In the hepatocyte, TCF7L2 risk alleles are associated with gain of function and increased hepatic glucose release during fasting (17). Recent studies suggest a possible regulatory role of a TCF7L2 variant on acyl-CoA synthetase long-chain family member 5 (ACSL5) expression and, thus, potentially on insulin sensitivity (20,21).…”

Section: Introductionmentioning

confidence: 99%

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

et al. 2017

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“…Transcription factor 7-like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) are strongly associated with type 2 diabetes risk, with about 30% increase per risk allele (3), and have been functionally linked to impaired insulin secretion, defects in incretin-and glucose-induced glucagon suppression, abnormal insulin processing, and increased hepatic glucose release during fasting (4)(5)(6). TCF7L2 variants also influence insulin sensitivity (7)(8)(9) and b-cell development (10,11). Similar findings have been demonstrated across different races (12,13).…”

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confidence: 99%

Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes

et al. 2018

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The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (‡2) autoantibody positivity, in relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ‡1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. RESULTS During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibodypositive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ‡1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ‡1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. CONCLUSIONS The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

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Cell free TCF7L2 gene alteration and their association with Type 2 diabetes mellitus in North Indian population

et al. 2020

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An alternative effector gene at the type 2 diabetes-associated TCF7L2 locus?

Cited by 7 publications

References 14 publications

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes

Cell free TCF7L2 gene alteration and their association with Type 2 diabetes mellitus in North Indian population

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