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TCF7L2 Variation Predicts Hyperglycemia Incidence in a French General Population

The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study

¹ CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France
² Regional Institute for Health, La Riche, France
³ Bichat Hospital, Paris, France
⁴ INSERM U695, Paris, France
⁵ INSERM U780-IFR69, Villejuif, France
⁶ University of Paris-Sud, Paris, France
⁷ Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K

Address correspondence and reprint requests to Philippe Froguel, Imperial College, Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.uk

Abbreviations: DESIR, Data from an Epidemiological Study on the Insulin Resistance Syndrome; HOMA, homeostasis model assessment; HOMA-B, HOMA of ß-cell function; HOMA-IR, HOMA of insulin resistance; IFG, impaired fasting glucose; PAR, population-attributable risk

Recently, case-control studies demonstrated that a TCF7L2 (transcription factor 7–like 2 gene) noncoding variant (rs7903146 T at-risk allele) was strongly associated with an increased risk of type 2 diabetes. However, the predictive value of this marker in a nonselected general population remains unknown. In this study, our aim was to assess the contribution of this variant to the prevalence and incidence of hyperglycemia (type 2 diabetes and impaired fasting glucose) and insulin regulation in a 9-year prospective study of 4,976 middle-aged participants in the French DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort. Our data support previous studies associating the T at-risk allele with a higher prevalence of hyperglycemia at baseline (P = 0.049) and a higher incidence of hyperglycemia after 9 years of follow-up (P = 0.014). The population-attributable risk to develop hyperglycemia due to the T at-risk allele was estimated to be 10.4% at the end of the prospective study. The most likely inheritance model was found to be additive (P = 0.002) rather than deviating from linearity (P = 0.098). An increase in the incidence of hyperglycemia was confirmed by survival analyses among C/C, C/T, and T/T carriers during the 9 years of follow-up (P = 0.028 by log-rank test). Interestingly, in control individuals, there was weak evidence of association of the T at-risk allele with reduced fasting insulin levels and insulin secretion index (homeostasis model assessment of ß-cell function) in control individuals. 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.

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