ArticleGenome medicine2017
Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells.
Article in Genome medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.
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Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 29 citations in OpenAlex.
- Contribution of Type 2 Diabetes Susceptible Gene GCKR Polymorphisms Rs780094 and Rs1260326 to Gestational Diabetes Mellitus: A Meta-AnalysisEndocrine, metabolic & immune disorders drug targets · 2026Pooled it
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.Human molecular genetics · 2018Trial
- Functional genomic analysis reveals HAVCR1 as the key regulator of 5q33.3 locus linked to hyperlipidemia.HGG advances · 2026Article
- FOXA2 in cancer: from fundamental biology to clinical translation.Frontiers in oncology · 2026Review
- Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases.Current issues in molecular biology · 2025Review
- Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response.International journal of molecular sciences · 2024Article
- Hormone and reproductive factors and risk of systemic lupus erythematosus: a Mendelian randomized study.Immunologic research · 2024Article
- Traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine.Journal of diabetes · 2024Review
- Advances in CRISPR-Cas technology and its applications: revolutionising precision medicine.Frontiers in genome editing · 2024Review
- The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326.Molecular metabolism · 2023Article
- Epigenetics of type 2 diabetes mellitus and weight change - a tool for precision medicine?Nature reviews. Endocrinology · 2022Review
- A common variant in 11q23.3 associated with hyperlipidemia is mediated by the binding and regulation of GATA4.NPJ genomic medicine · 2022Article
- Excess Heritability Contribution of Alcohol Consumption Variants in the "Missing Heritability" of Type 2 Diabetes Mellitus.International journal of molecular sciences · 2021Article
- Elevated circulating follistatin associates with an increased risk of type 2 diabetes.Nature communications · 2021Article
- Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases.International journal of molecular sciences · 2021Review
- Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases.International journal of molecular sciences · 2021Review
- Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.American journal of human genetics · 2021Article
- Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.Human molecular genetics · 2020Article
- Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia.Scientific reports · 2018Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGenome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094.
methodsWe used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies.
resultsThe ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver.
conclusionsOur results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.
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