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Cited by 118Genetic Syndromes and ImprintingPancreatic function and diabetesGenetic Associations and Epidemiology

Insights Into the Molecular Mechanism for Type 2 Diabetes Susceptibility at the KCNQ1 Locus From Temporal Changes in Imprinting Status in Human Islets

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Travers, Mary E., Mackay, Deborah J.G., Dekker Nitert, Marloes, Morris, Andrew P., Lindgren, Cecilia M., Berry, Andrew, Johnson, Paul R., Hanley, Neil +3 more·2013·Diabetes
DOI 10.2337/db12-0819PMC PMC3581222
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Abstract

The molecular basis of type 2 diabetes predisposition at most established susceptibility loci remains poorly understood. KCNQ1 maps within the 11p15.5 imprinted domain, a region with an established role in congenital growth phenotypes. Variants intronic to KCNQ1 influence diabetes susceptibility when maternally inherited. By use of quantitative PCR and pyrosequencing of human adult islet and fetal pancreas samples, we investigated the imprinting status of regional transcripts and aimed to determine whether type 2 diabetes risk alleles influence regional DNA methylation and gene expression. The results demonstrate that gene expression patterns differ by developmental stage. CDKN1C showed monoallelic expression in both adult and fetal tissue, whereas PHLDA2, SLC22A18, and SLC22A18AS were biallelically expressed in both tissues. Temporal changes in imprinting were observed for KCNQ1 and KCNQ1OT1, with monoallelic expression in fetal tissues and biallelic expression in adult samples. Genotype at the type 2 diabetes risk variant rs2237895 influenced methylation levels of regulatory sequence in fetal pancreas but without demonstrable effects on gene expression. We demonstrate that CDKN1C, KCNQ1, and KCNQ1OT1 are most likely to mediate diabetes susceptibility at the KCNQ1 locus and identify temporal differences in imprinting status and methylation effects, suggesting that diabetes risk effects may be mediated in early development.

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  • There is evidence that the T2DM risk associated with the KCNQ1 locus is mediated through another gene in the imprinted 11p15.5 region of the chromosome.

    “There is now evidence that the T2DM risk associated with the KCNQ1 locus is mediated through another gene in the imprinted 11p15.5 region of the chromosome (692).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [692]

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  1. [1]Hamming KS Soliman D Matemisz LC Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes 2009; 58: 2419– 2424 19587354 PMC2750221
  2. [2]Nicolson TJ Bellomo EA Wijesekara N Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 2009; 58: 2070– 2083 19542200 PMC2731533
  3. [3]Rees MG Wincovitch S Schultz J Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 2012; 55: 114– 122 22038520 PMC3276843
  4. [4]Beer NL Tribble ND McCulloch LJ The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 2009; 18: 4081– 4088 19643913 PMC2758140
  5. [5]Tsai FJ Yang CF Chen CC A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 2010; 6: e1000847 20174558 PMC2824763
  6. [6]Unoki H Takahashi A Kawaguchi T SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 2008; 40: 1098– 1102 18711366
  7. [7]Voight BF Scott LJ Steinthorsdottir V; MAGIC investigators; GIANT Consortium Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010; 42: 579– 589 20581827 PMC3080658
  8. [8]Yasuda K Miyake K Horikawa Y Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 2008; 40: 1092– 1097 18711367
  9. [9]Holmkvist J Banasik K Andersen G The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load. PLoS ONE 2009; 4: e5872 19516902 PMC2689931
  10. [10]Jonsson A Isomaa B Tuomi T A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. Diabetes 2009; 58: 2409– 2413 19584308 PMC2750226
  11. [11]Tan JT Nurbaya S Gardner D Ye S Tai ES Ng DP Genetic variation in KCNQ1 associates with fasting glucose and β-cell function: a study of 3,734 subjects comprising three ethnicities living in Singapore. Diabetes 2009; 58: 1445– 1449 19252135 PMC2682664
  12. [12]MacDonald PE Wheeler MB Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia 2003; 46: 1046– 1062 12830383
  13. [13]Jespersen T Grunnet M Olesen SP The KCNQ1 potassium channel: from gene to physiological function. Physiology (Bethesda) 2005; 20: 408– 416 16287990
  14. [14]Pan Q Ma J Zhou Q KCNQ1 loss-of-function mutation impairs gastric acid secretion in mice. Mol Biol Rep 2010; 37: 1329– 1333 19306073
  15. [17]Thakur N Tiwari VK Thomassin H An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region. Mol Cell Biol 2004; 24: 7855– 7862 15340049 PMC515059
  16. [18]Weksberg R Shuman C Beckwith JB Beckwith-Wiedemann syndrome. Eur J Hum Genet 2010; 18: 8– 14 19550435 PMC2987155
  17. [19]McMinn J Wei M Schupf N Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 2006; 27: 540– 549 16125225
  18. [20]Mackay DJ Callaway JL Marks SM Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 2008; 40: 949– 951 18622393
  19. [21]Arima T Kamikihara T Hayashida T ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome. Nucleic Acids Res 2005; 33: 2650– 2660 15888726 PMC1097765
  20. [22]Fitzpatrick GV Pugacheva EM Shin JY Allele-specific binding of CTCF to the multipartite imprinting control region KvDMR1. Mol Cell Biol 2007; 27: 2636– 2647 17242189 PMC1899897
  21. [23]Kassem SA Ariel I Thornton PS p57KIP2 expression in normal islet cells and in hyperinsulinism of infancy. Diabetes 2001; 50: 2763– 2769 11723059
  22. [24]Arboleda VA Lee H Parnaik R Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 2012; 44: 788– 792 22634751 PMC3386373
  23. [25]Redrup L Branco MR Perdeaux ER The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing. Development 2009; 136: 525– 530 19144718 PMC2685953

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Authors
Travers, M. E., Mackay, D. J. G., Dekker Nitert, M., Morris, A. P., Lindgren, C. M., Berry, A., Johnson, P. R., Hanley, N., Groop, L. C., McCarthy, M. I., & Gloyn, A. L.
Affiliations
  • University of Oxford (GB)
  • University of Southampton (GB)
  • Lund University Diabetes Centre, Malmö, Sweden;
  • Centre for Human Genetics (GB)
  • University of Manchester (GB)
  • Churchill Hospital (GB)
  • Lund University (SE)
Corresponding author
Gloyn, Anna L.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2013-02-14
Volume
62
Issue
3
Pages
987-992
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db12-0819
PMC
PMC3581222
OpenAlex
W2148201806
Cited by
118
References
2
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 9 · 2022: 7 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 15 · 2015: 11 · 2014: 20 · 2013: 3
FWCI
6.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • Wellcome Trust (088566, 098017, 095101, 095101/Z/10/Z, 090532)
  • National Institute for Health and Care Research (NF-SI-0611-10099)
  • Diabetes UK
  • European Foundation for the Study of Diabetes
  • Fondation pour la Recherche Médicale
  • Lunds Universitet
  • Vetenskapsrådet
  • European Association for the Study of Diabetes
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
type 2 diabetes risk, genomic imprinting, KCNQ1OT1, CDKN1C, PHLDA2, SLC22A18, DNA methylation, monoallelic expression, biallelic expression, fetal pancreas, developmental stages
MeSH terms
Adult, Alleles, Chromosomes, Human, Pair 11, Diabetes Mellitus, Type 2, United Kingdom, Humans, Introns, Islets of Langerhans, Pancreas, Cohort Studies, Gene Expression Regulation, Developmental, DNA Methylation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Fetal Development, Cyclin-Dependent Kinase Inhibitor p57, KCNQ1 Potassium Channel, Genetic Loci, Genetic Association Studies

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