This is the first report on TCF7L2
variation in a sample of well-characterised youth with type 2 diabetes and healthy controls in two racial/ethnic groups. We found a strong association among AA youth, with an effect size greater than previously seen in AA adults [2
]. No significant association was observed in NHW youth.
These data are consistent with a previous study in Finland among 11 young adults with incident type 2 diabetes (OR 10.9) suggesting that an association with TCF7L2
might have a more pronounced effect in participants with an earlier age at onset [8
]. A study in Colorado also identified that the allele and genotype frequencies of the two SNPs are associated (OR up to 4.0) with antibody-negative, but not antibody-positive diabetes with onset before age 25 years [9
]. The non-significant findings among NHW youth in our study may be the result of the relatively small sample of cases (n
=86). Several meta-analyses of data from multiple studies in adults estimated an allelic risk around 40% [1
], which is not inconsistent with the effect seen in NHW youth in our study (adjusted OR 1.09, 95% CI 0.70–1.70).
However, the effect of TCF7L2
on risk of adult onset type 2 diabetes was reported to be similar in NHW and AA populations [2
]. Estimates of allele frequencies for the T risk allele among our controls are consistent in both racial/ethnic groups and with other published reports in adults [1
], suggesting that our controls were reasonably representative of the NHW and AA in the USA. By virtue of their earlier age of onset of type 2 diabetes, youths may have higher frequencies of risk alleles than those seen in adult-onset cases. Our data suggest a greater contribution of TCF7L2
variation to early-onset type 2 diabetes among youths of AA origin. Nevertheless, our 95% CI (1.37–2.82) spans the published OR (~1.4), so we cannot state with certainty that the effect is stronger in younger AA people. In contrast, different genes and environmental factors may be more important contributors to early-onset type 2 diabetes among NHW youth. TCF7L2
variation leads to type 2 diabetes by an impairment in insulin secretion, rather than insulin resistance [10
]. Our findings that the association of TCF7L2
and type 2 diabetes in youth is independent of BMI, and the relationship between TCF7L2
variation and quantitative traits among controls are consistent with previous reports. A recent study has shown that the rs7903146 polymorphism modifies an enhancer element [11
]. The stronger effects seen for rs7903146 when compared with rs12255372 in AA youth supports the hypothesis that rs7903146 is a strong candidate for the functional variant. Our study was limited by the small number of NHW youth with type 2 diabetes, because of the relative rarity of the condition. Additionally, our conclusions are limited to NHW and AA youth. Although the SEARCH study includes other racial/ethnic groups (Hispanics, Asian/Pacific Islanders and Native Americans), the samples sizes were small and no appropriate control groups were available. We focused on TCF7L2
because it is the strongest type 2 diabetes association reported to date and the only one for which we had adequate statistical power. However, to date, our study is the largest case–control study of youth with type 2 diabetes that includes NHW and AA youth from a population-based study, with a well characterised phenotype.
In conclusion, TCF7L2 variation is strongly associated with an increased risk of early-onset type 2 diabetes among AA youth in the USA. This association is independent of obesity, with the effect size being larger than previously seen in adults. The stronger association between TCF7L2 variation and type 2 diabetes in AA youth than NHW youth suggests potential different contributions of genetic and/or environmental factors to early-onset type 2 diabetes in various racial/ethnic groups and requires further study.