TCF7L2 gene variants raise risk of type 2 diabetes

Studies in the Netherlands and India replicated research of other cohorts.

Issue: February 2007

Two new studies found that common variants of the TCF7L2 gene are strongly associated with an increased risk of type 2 diabetes mellitus.

Several previous studies have reported a correlation between certain single nucleotide polymorphisms (SNPs) of the TCF7L2 gene and an increased risk of type 2 diabetes. Researchers of two recently published studies sought to replicate these results: the first was a Dutch cohort study by Jana V. van Vliet-Ostaptchouk, PhD, of the Department of Molecular Genetics at Maastricht University in the Netherlands, et al; the second an Indian cohort study by Giriraj R. Chandak, MD, DNB, of the Center for Cellular and Molecular Biology in Hyderabad, India, and colleagues. Results of both were published in Diabetologia.

“The TCF7L2 gene encodes for an enteroendocrine transcription factor that has a role in the Wnt signaling pathway, which is one of the key developmental and growth regulatory mechanisms of the cell,” Vliet-Ostaptchouk and colleagues wrote. Because this gene transcriptionally regulates glucagon-like peptide 1 (GLP-1), variants of the gene “could influence the susceptibility to type 2 diabetes by altering levels of insulinotropic hormone GLP-1.”

The Dutch study comprising 502 people with type 2 diabetes from the Breda cohort as well as 920 healthy control patients. Genotyping found that the T allele of the rs12255372 SNP was more frequent among patients with type 2 diabetes than among control patients (34% vs. 29%; P=.003). Patients with diabetes were also more frequently homozygous for the T allele than control patients (12% vs. 9%; P=.03).

The rs7903146 SNP showed an even stronger correlation with type 2 diabetes. Thirty-seven percent of patients with diabetes had the T allele for this SNP vs. 29% of control patients (P=4.4×10^–5). With regard to genotype, 15% of patients with diabetes had the TT genotype compared to 9% of control patients (P=.0002).

Risks were consistently higher for homozygous than for heterozygous persons for both SNPs (OR 1.53, 95% CI 1.052.21 and OR 1.35, 95% CI 1.07–1.71 for rs12255372 and OR 1.96, 95% CI 1.37–2.80 and OR 1.37, 95% CI 1.08–1.73 for rs7903146, respectively),” the investigators wrote. “Moreover, the test for trend showed even stronger association of the disease with an increased number of minor alleles, especially for rs7903146 (P=6.6×10^–5), suggesting an alleledose effect.

The TT haplotype that carries the two minor alleles of both SNPs was found to be more common among those with diabetes than among control patients (33% vs. 26%, P=.00027). As the haplotype does not perform better than the rs7903146 SNP located in intron 3 of TCF7L2, this SNP can be used as a marker for type 2 diabetes risk,” the researchers wrote. Allele frequency data showed that individuals carrying the T allele had a “modest but significantly higher risk of developing type 2 diabetes.”

Overall, the data strongly suggested an association between TCF7L2 and type 2 diabetes in this cohort.

Indian cohort

Chandak and colleagues undertook their study to test if the previously reported associations between TCF7L2 and diabetes in Icelandic, European and American populations are similar among an Indian cohort. Type 2 diabetes has a prevalence between 12% and 16% among Indians living in cities, and India has the greatest number of people with diabetes in any single country.

The study included 955 patients at the Diabetology Research Centre at King Edward Memorial Hospital and Research Center in Pune, Maharashtra, Western India; researchers also enrolled 399 healthy, ethnically matched control patients. In this study, the same two SNPs were analyzed along with rs4506565, which the researchers wrote was the best correlated proxy of these SNPs.

“We found a strong association of TCF7L2 variants with type 2 diabetes mellitus in this Indian population, replicating observations in European populations,” the investigators wrote. Individuals who were homozygous for the risk alleles for all three SNPs had higher risk of having type 2 diabetes vs. control patients. This was most notable for the rs12255372 SNP, with heterozygotes having an OR of 1.43 (95% CI, 1.11-1.83) and homozygotes having an OR of 2.28 (95% CI, 1.40-3.72).

“As recent studies have suggested that the higher prevalence of type 2 diabetes mellitus in the South Asian Indians could be partially due to central obesity and altered distribution of fat and muscle mass, we investigated whether TCF7L2 genotypes were associated with altered BMI and [waist-hip ratio],” the researchers wrote. These analyses, however, found no significant associations between genotype and these anthropometric measures. Interestingly, among control patients, possessing the at-risk allele of rs12255372 predicted higher fasting and two-hour plasma glucose concentration and higher HOMA-IR; this suggests both a defect in insulin secretion from the beta cells and an increase in insulin resistance linked to this SNP.

Studies’ significance

“Our results show that the strongest risk variant found for type 2 diabetes mellitus to date in European populations is a risk allele of similar effect size in Indians and thus TCF7L2 is a major susceptibility gene for type 2 diabetes mellitus transgressing the boundaries of ethnicity, ” the researchers wrote. “This is consistent with genetic factors playing an important role in risk for type 2 diabetes mellitus, even in populations where environmental factors may have resulted in a dramatic recent increase in prevalence.” They noted that while the control group in this study could contain some patients who will later develop diabetes, this would result in a reduction in ORs and would imply that the strength of the association found might in fact be underestimated.

Van Vliet-Ostaptchouk and colleagues wrote that because the most strongly associated SNP is within an intron (non-coding part of the gene) of TCF7L2 it is unlikely to be the true disease variant. “However, the intronic variants may affect the level of gene expression by altering, for example, transcription, splicing or message stability. ... It will be of great interest to learn the molecular mechanisms of action of the TCF7L2 gene in the pathogenesis of type 2 diabetes and to identify potential targets for drugs that could be used for treatment and prevention of the disease due to the gene variants.” –by Dave Levitan

For more information:
Van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, et al. Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia. 2007; 10.1007/s00125-006-0477-z.
Chandak GR, Janipalli CS, Bhaskar S, et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia. 2007; 10.1007/s00125-006-0502-2.