ArticleEuropean journal of human genetics : EJHG2015
Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2.
Article in European journal of human genetics : EJHG, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 2 of them syntheses that pooled it.
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Who cites it
12 citing papers in PubMed, 2 syntheses or guidelines pooled it, 19 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis.Scientific reports · 2016Pooled it
- Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.Cellular and molecular life sciences : CMLS · 2024Review
- Polymorphic genetic markers and how they are associated with clinical and metabolic indicators of type 2 diabetes mellitus in the Kazakh population.Journal of diabetes and metabolic disorders · 2021Article
- Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation.Genome medicine · 2021Review
- Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.Frontiers in cardiovascular medicine · 2021Review
- TheDiabetes care · 2019Review
- Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors.Diabetes, metabolic syndrome and obesity : targets and therapy · 2019Review
- PARP-1 Inhibition Rescues Short Lifespan in HyperglycemicAging and disease · 2018Article
- Article
- The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5.Diabetologia · 2016Article
- The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1.PLoS genetics · 2016Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Resolving the underlying functional mechanism to a given genetic association has proven extremely challenging. However, the strongest associated type 2 diabetes (T2D) locus reported to date, TCF7L2, presents an opportunity for translational analyses, as many studies in multiple ethnicities strongly point to SNP rs7903146 in intron 3 as being the causal variant within this gene. We carried out oligo pull-down combined with mass spectrophotometry (MS) to elucidate the specific transcriptional machinery across this SNP using protein extracts from HCT116 cells. We observed that poly (ADP-ribose) polymerase 1 (PARP-1) is by far the most abundant binding factor. Pursuing the possibility of a feedback mechanism, we observed that PARP-1, along with the next most abundant binding proteins, DNA topoisomerase I and ATP-dependent RNA helicase A, dimerize with the TCF7L2 protein and with each other. We uncovered further evidence of a feedback mechanism using a luciferase reporter approach, including observing expression differences between alleles for rs7903146. We also found that there was an allelic difference in the MS results for proteins with less abundant binding, namely X-ray repair cross-complementing 5 and RPA/p70. Our results point to a protein complex binding across rs7903146 within TCF7L2 and suggests a possible mechanism by which this locus confers its T2D risk.
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