Analysis of the type 2 diabetes gene, TCF7L2, in 13,795 type 1 diabetes cases and control subjects

Abstract

To the Editor: The two most common forms of diabetes that have been classified are type 1 diabetes and type 2 diabetes. Type 1 diabetes is characterised by infiltration of the pancreas by autoreactive T cells and autoimmune destruction of pancreatic beta cells, leading to a complete loss of insulin production, whereas type 2 diabetes is associated with the gradual increase of insulin insensitivity in tissues leading to hyperglycaemia and beta cell failure. However, it has been suggested that type 1 diabetes and type 2 diabetes may share a common genetic aetiology [1]. For example, the accelerator hypothesis suggests that type 1 diabetes and type 2 diabetes are the same disease of hyperglycaemiainduced beta cell damage but that type 1 diabetes has the added effect of autoimmunity [1]. One way of testing the hypothesis that there is a common causal pathway between type 1 and type 2 diabetes is to analyse a type 2 diabetes gene with a large effect in a large type 1 diabetes sample. Until very recently [2] this has not been possible, as no such locus has emerged from type 2 diabetes genetics studies. Recently, however, the transcription-factor-7-like 2 (TCF7L2) gene region on chromosome 10q25.2 has been found to contribute substantially to the risk of type 2 diabetes with convincing statistical support (relative risk [RR]=0.67; p=2.1×10 for the 0 allele of the microsatellite marker DG10S478) [2]. This study was carried out in three different populations: Icelandic, Danish and white American. Two single nucleotide polymorphisms (SNPs) were also genotyped in this study: rs12255372 (G>T, minor allele frequency [MAF] 0.36 in control subjects) and rs7903146 (C>T, MAF=0.28 in control subjects). rs12255372 was found to be in high linkage disequilibrium (LD) with DG10S478 (r=0.95 for the major G allele of the SNP with the 0 allele of the microsatellite marker). rs7903146 was in lower LD with the DG10S478 (r=0.75): for the minor allele (T) of this SNP the authors obtained odds ratios (ORs) of 1.41–1.71 in the three populations and p values from 0.0018 to 1.6×10 [2]. These results were independently replicated in 2,158 white UK type 2 diabetic subjects, 2,574 geographically matched white control subjects and 388 parent–offspring trios [3]. In this population it was found that the T allele of rs7903146 was the most associated with type 2 diabetes susceptibility (OR=1.36, 95% CI=1.24–1.48 and p=3.6× 10, MAF=0.31 in control subjects), but that the T allele of rs12255372 was also associated (OR=1.29, 95% CI= 1.18–1.41; p=2.2×10, MAF=0.30 in control subjects) [3]. These results have also been confirmed by other studies in Finnish and US populations [4, 5]. A study on type 2 diabetes progression suggests that TCF7L2 may be associated with insulin secretion [6]. Therefore, as TCF7L2 is a major gene in type 2 diabetes we can now test if it affects type 1 diabetes susceptibility. We analysed the two SNPs, rs12255372 and rs7903146, in 6,199 white UK type 1 diabetic subjects (5,872 from the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory’s Genetic Resource Diabetologia (2007) 50:212–213 DOI 10.1007/s00125-006-0506-y