| COMMENTARIES |
Association between TCF7L2 Polymorphism and Diabetes Mellitus, Metabolic Syndrome, and Markers of Beta Cell Function and Insulin Resistance
Hussein Saadi1 and Nicolaas Nagelkerke2, 1Departments of Internal Medicine and 2Community Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P O Box 17666, Al Ain, United Arab Emirates
Background
Type 2 diabetes mellitus (DM) is one of the most common chronic diseases and affects more than 6% of the world’s population. The prevalence of DM is on the increase in many parts of the world and has been estimated to reach 300 million by the year 2025 [1]. This has been attributed to rising prevalence of obesity due to an abundance of food and chronic lack of exercise, acting on genetically susceptible individuals. Inevitably this will lead to high rates of cardiovascular disease, stroke, blindness, amputations, and other complications. However, not all individuals are equally susceptible to diabetes under these unfavorable environmental conditions. Differences in the genetic make-up of people, and perhaps also differences in early-life conditions, must account for this. Finding genes associated with the development of diabetes potentially offers avenues for screening, diagnostics, and therapeutics. For example, those found to be at very high genetic risk may be more motivated to diet, exercise, and reduce other risk factors than those known to have a low risk. In view of the potential importance of such genes, identifying polymorphisms in genes (“gene hunting”) linked to diabetes risk is currently an active field of research, although most of the genes involved have not yet been determined. The strongest known association between DM and genetic markers is that with the recently mapped single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2), a gene located on chromosome 10q25 [2]. TCF7L2 is a member of the T-cell factor (TCF)/lymphoid-enhancing factor family of high mobility group box-containing transcription factors involved in the Wnt signaling pathway, a pathway that plays a key role in the regulation of cell proliferation and differentiation, thereby exerting an influence on a large variety of functions in the cell [3-5]. TCF7L2 is also implicated in a variety of diseases, including DM and various cancers. A recent genome-wide study confirmed the above reported association with DM and identified significant associations for few other susceptibility loci [6]. It is unknown, however, whether the association of this gene with diabetes is confined to specific populations or whether it has more universal validity.
Methods and Results
We recently analyzed the associations between TCF7L2 polymorphism and DM, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects [7]. The prevalence of DM among Emirati subjects is one of the highest in the world [1,8,9]. The two TCF7L2 single nucleotide polymorphisms (SNPs), rs12255372 (having T and G variants) and rs7903146 (having C and T variants), were genotyped in 368 adult subjects, identified in a population survey on DM and its risk factors and complications. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA2-%B) and insulin resistance (HOMA2-IR). The SNP genotypes were analyzed against disease stage [normal glucose = 0 (n = 188), pre-diabetes = 1 (n = 85), and DM = 2 (n = 95)] and against clinical and biochemical measures. Diabetes disease stage was marginally significantly associated with the frequency of the T variant at rs12255372 (p = 0.057; adjusted p = 0.017) but not at rs7903146 (p = 0.5; adjusted p = 0.2). Comparison between subjects with normal glucose and the combined DM/pre-diabetes showed a significant association with rs12255372 (OR 1.47, CI 1.04-2.08; p = 0.03) but not with rs7903146 (OR 1.16, CI 0.81-1.64; p = 0.4). We found no association with insulin and glucose levels, HOMA2-%B or HOMA2-IR. We also found no association with metabolic syndrome or diabetic complications except for coronary heart disease which was slightly (but statistically not significantly) more frequent in the risk (T) allele homozygotes of rs7903146 (5.4% versus 4.9% versus 19.0%; p = 0.08) and rs12255372 (4.9% versus 5.3% versus 16.0%; p = 0.06). These data suggest that TCF7L2 variants are associated with increased risk for DM and possibly coronary heart disease in Emirati subjects.
Conclusions
As yet, the immediate clinical applications of the association between gene polymorphism and DM include early identification of subjects at risk for diabetes mellitus and its complications. Additionally lifestyle intervention has been shown to efficiently reduce the risk conferred by these genetic variants [10,11]. Further research should identify the biochemical pathways mediating this association. Eventually, a better understanding of the biochemical pathways involved may suggest methods of therapeutic interventions, e.g. by chemically blocking or stimulating certain pathways.
References