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

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


Author Travers, Mary E.
Mackay, Deborah J. G.
Dekker Nitert, Marloes
Morris, Andrew P.
Lindgren, Cecilia M.
Berry, Andrew
Johnson, Paul R.
Hanley, Neil
Groop, Leif C.
McCarthy, Mark I.
Gloyn, Anna L.
Title Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets
Formatted title
Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2013-03-01
Year available 2012
Sub-type Article (original research)
DOI 10.2337/db12-0819
Volume 62
Issue 3
Start page 987
End page 992
Total pages 6
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Collection year 2013
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Thu, 07 Mar 2013, 22:03:03 EST by Marloes Dekker on behalf of Royal Brisbane Clinical School