TCF7L2 gene variants increase risk of developing type 2 diabetes

Participants in the Diabetes Prevention Program with certain genotypes had impaired beta-cell function.

Issue: August 2006

A study of participants in the Diabetes Prevention Program found that two variants of the transcription factor 7-like 2 gene were associated with an increased risk of developing type 2 diabetes.

“The risk of type 2 diabetes is strongly influenced by inheritance. … Despite important advances in understanding the genetic determinants of the relatively rare monogenic forms of diabetes, the pace of definitive identification of genes that increase the risk of common type 2 diabetes has been slow,” researchers wrote in the New England Journal of Medicine.

This new research, however, has confirmed that two single-nucleotide polymorphisms (rs12255372 and rs7903146) of the transcription factor 7-like 2 gene (TCF7L2) are associated with type 2 diabetes.

Jose C. Florez, MD, PhD, an endocrinologist at Massachusetts General Hospital and instructor in medicine at Harvard Medical School in Boston, and colleagues genotyped those two variants in 3,548 participants in the Diabetes Prevention Program (DPP) to evaluate the association with type 2 diabetes and to assess the effects of the gene variants on the interventions used in the DPP. They also analyzed the variants’ effects on insulin secretion and insulin sensitivity.

Study characteristics

Of the 3,548 participants, all had impaired glucose tolerance and were initially assigned to placebo, lifestyle intervention or metformin. Of these participants, 56.4% were white, 20.2% were black, 16.8% were Hispanic, 4.3% were Asian and 2.4% were American Indian.

Similar numbers of individuals were found to have the potentially risk-conferring TT genotype for both rs12255372 and rs7903146.

Analyses showed that those who were TT homozygous at rs7903146 were more likely to progress to type 2 diabetes than those who were homozygous for the C allele (HR 1.55; 95% CI, 1.20-2.01). Researchers noted that “no excess risk was conferred by the heterozygous genotype, although heterozygous individuals did have measurable defects in insulin secretion.”

The TT genotype incurred the greatest risk among DPP participants in the placebo group (HR 1.81; 95% CI, 1.21-2.70), and less in the metformin group (HR 1.62; 95% CI, 1.03-2.54) and the lifestyle intervention group (HR 1.15; 95% CI, 0.68-1.94). In the placebo group, researchers found an incidence of diabetes for the TT, CT and CC genotypes of 18.5, 10.7 and 10.8 per 1,000 person-years, respectively.

With regard to the risk-conferring TT genotype at rs12255372, results were similar.

Quantitative traits

Researchers also examined if genotype affected quantitative glycemic traits. They found that carriers of the T allele at both single-nucleotide polymorphisms had lower levels of insulin secretion vs. those who were homozygous for the C allele. They also found impaired beta-cell function among TT homozygotes, as well as greater mean insulin sensitivity.

“Our data indicate that the risk alleles in rs7903146 and rs12255372 predict the risk of diabetes prospectively, beyond that conferred by the clinical risk factors reflected by the DPP eligibility criteria,” the researchers wrote.

Notably, investigators did not find significant interactions between genotype and intervention at either polymorphism.

Genotype-intervention interactions

“The absence of an effect may not be surprising, since these interventions succeeded primarily by improving insulin sensitivity and these variants affect insulin secretion.” They did note, however, that the lack of an effect of the genotype on those in the lifestyle intervention group suggests that behavioral changes can “mitigate the risk conferred by genetic background.”

Florez stressed in a news release that further studies are clearly needed to elucidate the potential uses of this research. “Our data, combined with previous longitudinal studies and genetic findings, show that type 2 diabetes can be triggered by decreased insulin production and not just by insulin resistance,” he said. Understandings of the mechanisms by which these gene variants affect glucose homeostasis may provide opportunities for targeted interventions. – by Dave Levitan

For more information:

Florez JC, Jablonski KA, Bayley N, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006;355:241-250.