Context: Variants in the transcription factor 7-like2 (TCF7L2)-gene have been associated with increased risk for type 2 diabetes in adults. To evaluate whether the five reported risk variants confer a higher risk for obesity and early impairment of glucose metabolism in children, we genotyped these risk variants of the TCF7L2-gene in a representative cohort of 1029 Caucasian children and an independent cohort of 283 obese children.

Results: Applying a case control design, we observed a significantly lower prevalence of the rs11196205 and rs7895340 risk alleles in the obese (n=283) compared to lean (n=672) children (0.40 vs. 0.45,P=0.02). There was, however, no statistical significant relationship between these genotypes and quantitative traits of obesity in neither a normal representative (n=1029) nor obesity cohort. Obese children were significantly taller than lean children. This increase in height was independently associated with risk variants of the TCF7L2-gene, while in the normal representative cohort height appeared to be decreased in carriers of the minor alleles. In the obese cohort, three risk alleles (rs7901695, rs7903146, rs1225572) were significantly associated with higher fasting and 120-min blood glucose levels independent of sex, age, pubertal stage, and BMI. Fasting and peak insulin levels and HOMA-IR appeared with a similar tendency but were not statistically significant.

Conclusions: Our data indicate for the first time that TCF7L2-gene variants confer an increased risk for early impairment of glucose metabolism in obese children, which is consistent with adult studies identifying TCF7L2 as a major diabetes susceptibility gene.