We conclude that the TCF7L2 T at-risk allele variation (rs7903146) predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion.
Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity (p = 0.004).
The T-allele of TCF7L2 rs7903146 polymorphism was independently associated with increasing fasting glucose values toward hyperglycemia in the follow-up.
Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02).
Also the well-known gene variants rs7903146 in TCF7L2, and rs17817449 in FTO, were nominally associated with hyperglycemia (rs7903146), as well as with higher fasting insulin levels (rs17817449).
There were significant linear interactions between rs7903146 and BMI/WC and elevated blood glucose (P < 0.001); rs290487 and BMI/WC also showed a linear interaction with blood glucose levels (P < 0.001).