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Assessment of the role of genetic variation in the transient neonatal diabetes (TNDM) region on chromosome 6q24 in type 2 diabetes: a comparative genomic and haplotype approach

Assessment of the role of genetic variation in the transient neonatal diabetes (TNDM) region on chromosome 6q24 in type 2 diabetes: a comparative genomic and haplotype approach
Assessment of the role of genetic variation in the transient neonatal diabetes (TNDM) region on chromosome 6q24 in type 2 diabetes: a comparative genomic and haplotype approach
Background & Aims: Recent reports have supported the hypothesis that genes involved in monogenic forms of diabetes make excellent candidate genes for type 2 diabetes.Transient neonatal diabetes (TNDM) is a rare disorder associated with overexpression of genes at a paternally-expressed imprinted locus on chromosome 6q24, the key candidate gene being the transcription factor ZAC. Several type 2 diabetes linkage studies have indicated linkage to chromosome 6q22-25, in one case with evidence of overtransmission of paternal alleles. We hypothesised that common genetic variation at this TNDM region could influence susceptibility to type 2 diabetes. Materials & Methods: Comparative genomic analysis was used to identify common variants within the ZAC region, from which its haplotype structure was derived. Results: Seven SNPs with minor allele frequencies ranging from 15–46%, which captured the 5 most common haplotypes were genotyped in a largescale case-control (n=3643) and family based (n=520 families) study. This sample size had >80% power to detect odds ratios of >1.2 for all tagging SNPs. None of the 7 SNPs nor the haplotypes formed by these SNPs were associated with diabetes in our case control study (global p values for haplotype blocks 1 & 2 respectively = 0.81, 0.74). Nor did we find evidence for over transmission of any SNP or haplotype to affected offspring (global p values for blocks 1 & 2 = 0.09, 0.17), or for a parent of origin effect (p values ranged between 0.03–1 for the 7 SNPs). Conclusions: We conclude that common genetic variation at this locus is unlikely to influence susceptibility to Type 2 diabetes, although we cannot exclude a parent of origin effect with modest effect size. Support: Diabetes UK
england, time, london, diabetes, role, neonatal diabetes
0012-186X
p.A119
Gloyn, A.L.
d1f87f65-4420-418e-819b-5cb997b36597
Mackay, D.J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Weedon, M.N.
8329c1b5-6d81-40be-8b20-2e884dc93660
McCarthy, M.I.
050fe4a4-e91d-43cd-ad4c-a31a557094b3
Walker, M.
55b11dc5-60f7-4a90-940a-e89c785c7b93
Hitman, G.
d61e9c41-12e8-4367-a254-2af2d5056400
Sampson, M.
9a7da298-adbf-4de4-acd0-aeaebc99ea6f
Knight, B.A.
f1ea530f-8457-4203-b7a6-5ace8e3b9d48
Hattersley, A.T.
c555d835-dd08-415c-be14-26940d5c582d
Frayling, T.M.
eb989fcd-1dec-478c-912e-73013ba6a63d
Gloyn, A.L.
d1f87f65-4420-418e-819b-5cb997b36597
Mackay, D.J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Weedon, M.N.
8329c1b5-6d81-40be-8b20-2e884dc93660
McCarthy, M.I.
050fe4a4-e91d-43cd-ad4c-a31a557094b3
Walker, M.
55b11dc5-60f7-4a90-940a-e89c785c7b93
Hitman, G.
d61e9c41-12e8-4367-a254-2af2d5056400
Sampson, M.
9a7da298-adbf-4de4-acd0-aeaebc99ea6f
Knight, B.A.
f1ea530f-8457-4203-b7a6-5ace8e3b9d48
Hattersley, A.T.
c555d835-dd08-415c-be14-26940d5c582d
Frayling, T.M.
eb989fcd-1dec-478c-912e-73013ba6a63d

Gloyn, A.L., Mackay, D.J.G., Weedon, M.N., McCarthy, M.I., Walker, M., Hitman, G., Sampson, M., Knight, B.A., Hattersley, A.T. and Frayling, T.M. (2005) Assessment of the role of genetic variation in the transient neonatal diabetes (TNDM) region on chromosome 6q24 in type 2 diabetes: a comparative genomic and haplotype approach. Diabetologia, 48 (Supplement 1), p.A119.

Record type: Article

Abstract

Background & Aims: Recent reports have supported the hypothesis that genes involved in monogenic forms of diabetes make excellent candidate genes for type 2 diabetes.Transient neonatal diabetes (TNDM) is a rare disorder associated with overexpression of genes at a paternally-expressed imprinted locus on chromosome 6q24, the key candidate gene being the transcription factor ZAC. Several type 2 diabetes linkage studies have indicated linkage to chromosome 6q22-25, in one case with evidence of overtransmission of paternal alleles. We hypothesised that common genetic variation at this TNDM region could influence susceptibility to type 2 diabetes. Materials & Methods: Comparative genomic analysis was used to identify common variants within the ZAC region, from which its haplotype structure was derived. Results: Seven SNPs with minor allele frequencies ranging from 15–46%, which captured the 5 most common haplotypes were genotyped in a largescale case-control (n=3643) and family based (n=520 families) study. This sample size had >80% power to detect odds ratios of >1.2 for all tagging SNPs. None of the 7 SNPs nor the haplotypes formed by these SNPs were associated with diabetes in our case control study (global p values for haplotype blocks 1 & 2 respectively = 0.81, 0.74). Nor did we find evidence for over transmission of any SNP or haplotype to affected offspring (global p values for blocks 1 & 2 = 0.09, 0.17), or for a parent of origin effect (p values ranged between 0.03–1 for the 7 SNPs). Conclusions: We conclude that common genetic variation at this locus is unlikely to influence susceptibility to Type 2 diabetes, although we cannot exclude a parent of origin effect with modest effect size. Support: Diabetes UK

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More information

Published date: September 2005
Additional Information: PS 7: Monogenic forms of diabetes (314)
Keywords: england, time, london, diabetes, role, neonatal diabetes

Identifiers

Local EPrints ID: 59761
URI: http://eprints.soton.ac.uk/id/eprint/59761
ISSN: 0012-186X
PURE UUID: c4d80c73-8c31-425a-aeaf-29548a725a3f
ORCID for D.J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 17 Mar 2009
Last modified: 28 Jul 2020 01:34

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Contributors

Author: A.L. Gloyn
Author: D.J.G. Mackay ORCID iD
Author: M.N. Weedon
Author: M.I. McCarthy
Author: M. Walker
Author: G. Hitman
Author: M. Sampson
Author: B.A. Knight
Author: A.T. Hattersley
Author: T.M. Frayling

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