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

Context: Variants in the transcription factor 7-like2 (TCF7L2) gene have been associated with an 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 with lean (n=672) children (0.40 vs. 0.45; P=0.02). There was, however, no statistically significant relationship between these genotypes and quantitative traits of obesity in either a normal representative cohort (n=1029) or an obesity cohort. Obese children were significantly taller than lean children. This increase in height was independently associated with risk variants of the TCF7L2 gene, whereas 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, and rs1225572) were significantly associated with higher fasting and 120-min blood glucose levels independent of sex, age, pubertal stage, and body mass index. 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.