TCF7L2-gene polymorphisms confer an increased risk for early impairment of glucose metabolism and increased height in obese children

Variants in the TCF7L2-gene have been associated with increased risk for type 2 diabetes in adults. To evaluate whether these risk variants confer a higher risk for obesity and early impairment of glucose metabolism in children, we genotyped five risk variants of the TCF7L2-gene in a representative cohort of 1029 Caucasian children and in an independent cohort of 283 obese children. Applying a case control design, we observed a significantly lower prevalence of the rs11196205 and rs7895340 risk alleles in the obese compared to lean 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 the schoolchildren nor obesity cohort. Along with the marked elevation in BMI in obese children, they 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. This increase in height may be phenomenal for the constitutional (growth) acceleration frequently seen in obese children that has been discussed as potentially accelerating diabetes manifestation along with autoimmunity and insulin resistance in the „accelerator hypothesis“. In the obese cohort, three risk alleles (rs7901695, rs7903146, rs1225572) were significantly associated with higher fasting and stimulated blood glucose levels independent of sex, age, pubertal stage, height, and BMI. Quantitative traits of insulin secretion appeared with a similar tendency but were not statistically significant.

Hence, 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.