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

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.

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 over transmission 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 structurewas derived.Results: Seven SNPs with minor allele frequencies ranging from 15–46%, which captured the 5 most common haplotypes were genotyped in a large scale 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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Contributors

Author: D.J.G. Mackay

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