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Insights into the molecular mechanism for Type 2 diabetes susceptibility at the KCNQ1 locus From temporal changes in imprinting status in human islets

Insights into the molecular mechanism for Type 2 diabetes susceptibility at the KCNQ1 locus From temporal changes in imprinting status in human islets
Insights into the molecular mechanism for Type 2 diabetes susceptibility at the KCNQ1 locus From temporal changes in imprinting status in human islets
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.

0012-1797
987-992
Travers, M. E.
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Mackay, D. J. G.
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Nitert, M. D.
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Morris, A. P.
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Lindgren, C. M.
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Berry, A.
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Johnson, P. R.
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Hanley, N.
f64325bc-b0ed-4249-8f11-dbe4cdcbff93
Groop, L. C.
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McCarthy, M. I.
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Gloyn, A. L.
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Travers, M. E.
87abf9d6-2046-4ff9-a45f-7f6d8ed5661a
Mackay, D. J. G.
588a653e-9785-4a00-be71-4e547850ee4a
Nitert, M. D.
a107244e-2b13-47e3-a8a1-1825b97b41ac
Morris, A. P.
148266ca-f7ff-45bf-9dab-3ca8fb89e804
Lindgren, C. M.
93f3b501-e75c-41f7-8ce6-84f3f98d2022
Berry, A.
b75320e3-947d-4f4b-b2fb-374aadda9793
Johnson, P. R.
907eae1c-d944-44d4-9656-d759383a9c5d
Hanley, N.
f64325bc-b0ed-4249-8f11-dbe4cdcbff93
Groop, L. C.
908e5e3c-9bac-41f7-9880-6ff88ee7aeee
McCarthy, M. I.
c051b1da-5a4e-444b-aa39-1d69c0d4487d
Gloyn, A. L.
fb614845-c698-497f-9f22-b35877481991

Travers, M. E., Mackay, D. J. G., Nitert, M. D., Morris, A. P., Lindgren, C. M., Berry, A., Johnson, P. R., Hanley, N., Groop, L. C., McCarthy, M. I. and Gloyn, A. L. (2013) Insights into the molecular mechanism for Type 2 diabetes susceptibility at the KCNQ1 locus From temporal changes in imprinting status in human islets. Diabetes, 62 (3), 987-992. (doi:10.2337/db12-0819).

Record type: Article

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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More information

e-pub ahead of print date: 8 November 2012
Published date: March 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 345166
URI: http://eprints.soton.ac.uk/id/eprint/345166
ISSN: 0012-1797
PURE UUID: 4c4c953a-9cbe-4a98-a046-a776a81f1e68
ORCID for D. J. G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

Catalogue record

Date deposited: 12 Nov 2012 14:34
Last modified: 23 Jul 2022 01:44

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Contributors

Author: M. E. Travers
Author: D. J. G. Mackay ORCID iD
Author: M. D. Nitert
Author: A. P. Morris
Author: C. M. Lindgren
Author: A. Berry
Author: P. R. Johnson
Author: N. Hanley
Author: L. C. Groop
Author: M. I. McCarthy
Author: A. L. Gloyn

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