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Assessment of the Role of Common Genetic Variation in the Transient Neonatal Diabetes Mellitus (TNDM) Region in Type 2 Diabetes

A Comparative Genomic and Tagging Single Nucleotide Polymorphism Approach

¹ Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, U.K
² Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
³ Wessex Regional Genetics Laboratories, Salisbury District Hospital, Salisbury, U.K
⁴ Department of Medicine, School of Medicine, University of Newcastle, Newcastle, U.K
⁵ Centre of Diabetes & Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K

Address correspondence and reprint requests to Dr. Timothy M. Frayling St. Lukes Laboratories, Peninsula Medical School, Magdalen Road, Exeter, EX1 2LU, U.K. E-mail: tim.frayling{at}pms.ac.uk

Abbreviations: HWE, Hardy-Weinberg equilibrium; MAF, minor allele frequency; SNP, single nucleotide polymorphism; TNDM, transient neonatal diabetes mellitus; tSNP, tag SNP

Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22–25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of <1.2, we conclude that common variation in the TNDM region does not play an important role in the genetic susceptibility to type 2 diabetes.

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