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

Mary E. Travers; Deborah J G Mackay; Marloes Dekker Nitert; Andrew P. Morris; Cecilia M. Lindgren; Andrew Berry; Paul R. Johnson; Neil Hanley; Leif C. Groop; Mark I. McCarthy; Anna L. Gloyna

doi:10.2337/db12-0819

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

Mary E. Travers, Deborah J G Mackay, Marloes Dekker Nitert, Andrew P. Morris, Cecilia M. Lindgren, Andrew Berry, Paul R. Johnson, Neil Hanley, Leif C. Groop, Mark I. McCarthy, Anna L. Gloyna

Research output: Contribution to journal › Article › peer-review

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. Copyright © 2013 by the American Diabetes Association.

Original language	English
Pages (from-to)	987-992
Number of pages	5
Journal	Diabetes
Volume	62
Issue number	3
DOIs	https://doi.org/10.2337/db12-0819
Publication status	Published - Mar 2013

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http://diabetes.diabetesjournals.org/content/62/3/987.full.pdf

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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., & Gloyna, 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. https://doi.org/10.2337/db12-0819

@article{e9c839c81417426f9cf297aa10348745,

title = "Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets",

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. Copyright {\textcopyright} 2013 by the American Diabetes Association.",

author = "Travers, {Mary E.} and Mackay, {Deborah J G} and Nitert, {Marloes Dekker} and Morris, {Andrew P.} and Lindgren, {Cecilia M.} and Andrew Berry and Johnson, {Paul R.} and Neil Hanley and Groop, {Leif C.} and McCarthy, {Mark I.} and Gloyna, {Anna L.}",

year = "2013",

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doi = "10.2337/db12-0819",

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AU - Travers, Mary E.

AU - Mackay, Deborah J G

AU - Nitert, Marloes Dekker

AU - Morris, Andrew P.

AU - Lindgren, Cecilia M.

AU - Berry, Andrew

AU - Johnson, Paul R.

AU - Hanley, Neil

AU - Groop, Leif C.

AU - McCarthy, Mark I.

AU - Gloyna, Anna L.

PY - 2013/3

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N2 - 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. Copyright © 2013 by the American Diabetes Association.

AB - 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. Copyright © 2013 by the American Diabetes Association.

U2 - 10.2337/db12-0819

DO - 10.2337/db12-0819

M3 - Article

SN - 0012-1797

SN - 1939-327X

VL - 62

SP - 987

EP - 992

JO - Diabetes

JF - Diabetes

IS - 3

ER -

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

Abstract

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