Dataset Information

The TCF7L2 Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes.

ABSTRACT: Over the past ?15 years there has been great progress in our understanding of the genetics of both type 1 diabetes and type 2 diabetes. This has been driven principally by genome-wide association studies (GWAS) in increasingly larger sample sizes, where many distinct loci have now been reported for both traits. One of the loci that dominates these studies is the TCF7L2 locus for type 2 diabetes. This genetic signal has been leveraged to explore multiple aspects of disease risk, including developments in genetic risk scores, genetic commonalities with cancer, and for gaining insights into diabetes-related molecular pathways. Furthermore, the TCF7L2 locus has aided in providing insights into the genetics of both latent autoimmune diabetes in adults and various presentations of type 1 diabetes. This review outlines the knowledge gained to date and highlights how work with this locus leads the way in guiding how many other genetic loci could be similarly used to gain insights into the pathogenesis of diabetes.

SUBMITTER: Grant SFA

PROVIDER: S-EPMC6702598 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The <i>TCF7L2</i> Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes.

Grant Struan F A SFA

Diabetes care 20190813 9

Over the past ∼15 years there has been great progress in our understanding of the genetics of both type 1 diabetes and type 2 diabetes. This has been driven principally by genome-wide association studies (GWAS) in increasingly larger sample sizes, where many distinct loci have now been reported for both traits. One of the loci that dominates these studies is the <i>TCF7L2</i> locus for type 2 diabetes. This genetic signal has been leveraged to explore multiple aspects of disease risk, including ...[more]

PMID: 31409726

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Project description:TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2). Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.

Project description:Hereditary Multiple Exostoses (HME) is an autosomal-dominant disorder characterized by benign cartilage tumors (exostoses) forming near the growth plates, leading to severe health problems. EXT1 and EXT2 are the two genes known to harbor heterozygous loss-of-function mutations that account for the vast majority of the primary genetic component of HME. However, patients present with wide clinical heterogeneity, suggesting that modifier genes play a role in determining severity. Our previous work has pointed to an imbalance of β-catenin signaling being involved in the pathogenesis of osteochondroma formation. TCF7L2 is one of the key 'gate-keeper' TCF family members for Wnt/β-catenin signaling pathway, and TCF7L2 and EXT2 are among the earliest associated loci reported in genome wide appraisals of type 2 diabetes (T2D). Thus we investigated if the key T allele of single nucleotide polymorphism (SNP) rs7903146 within the TCF7L2 locus, which is strongly over-represented among T2D cases, was also associated with HME. We leveraged genotype data available from ongoing GWAS efforts from genomics and orthopedic centers in the US, Canada and Italy. Collectively 213 cases and 1890 controls were analyzed and, surprisingly, the T allele was in fact significantly under-represented in the HME patient group [P = 0.009; odds ratio = 0.737 (95% C.I. 0.587-0.926)]; in addition, the direction of effect was consistent within each individual cohort. Immunohistochemical analyses revealed that TCF7L2 is differentially expressed and distributed in normal human growth plate zones, and exhibits substantial variability in human exostoses in terms of staining intensity and distribution. In summary, the data indicate that there is a putative genetic connection between TCF7L2 and EXT in the context of HME. Given this observation, we suggest that these loci could possibly modulate shared pathways, in particular with respect to β-catenin, and their respective variants interplay to influence HME pathogenesis as well as T2D.

Dataset Information

The TCF7L2 Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes.

Publications

The <i>TCF7L2</i> Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes.

Similar Datasets

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