14 November 2006
A new publication by Humphries et al. in the Journal of Molecular Medicine examines the association between two common variants in the TCF7L2 gene and type 2 diabetes (T2D). This study follows up earlier work conducted by Grant et al. in Icelandic, Danish and European-American populations (see our rapid response to this earlier study). Humphries et al. investigate the role of these two variants in three well established cohort studies of European White, Indian Asian and Afro-Caribbean origin.
The study used both prospective and case-control designs to compare the risk association between the different genotypes in T2D cohorts of the three ethnic groups with non-diabetic ethnically-matched subjects. Subjects were adjusted for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels. One of the two gene variants (IVS3C>T) was found to nearly double the risk of T2D, and the other (IVS4G>T) was found to have a smaller, but still significant effect across all three groups. The authors speculate that the mechanism by which the TCF7L2 gene affects T2D risk may be due to alterations in Wnt signalling, since TCF7L2 is a transcription factor in this pathway, but the study did not investigate this.
Comment: The study is well presented and provides external replication of the earlier findings by Grant et al. in three additional population groups further strengthening the support for the possible role of the TCF7L2 gene in T2D. The authors report possible limitations in their study, such as the small number of individuals who developed T2D, and also stress that the data presented for the Afro-Caribbean subset should only be regarded as preliminary. In addition to this they also report that further research is warranted into both the risk variants within the TCF7L2 gene and the mechanism by which the risk of T2D is altered. Once the risk variants and molecular pathway/s by which they act have been identified, specific treatments can be tailored to the carriers of the causal defect(s), and although these studies provide very exciting evidence for the role of TCF7L2, at this stage the prospect of treatments is still somewhat distant.
This article was written by Gurdeep Sagoo and Simon Leese.