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Title: Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population

Author
item CORELLA, DOLORES - University Of Valencia
item CARRASCO, PAULA - University Of Valencia
item SORLÍ, JOSE - University Of Valencia
item ESTRUCH, RAMON - Instituto De Salud Carlos Iii
item RICO-SANZ, JESUS - University Of Valencia
item MARTINEZ-GONZALEZ, MIGUEL ANGEL - Instituto De Salud Carlos Iii
item SALAS-SALVADO, JORDI - Instituto De Salud Carlos Iii
item COVAS, M. ISABEL - Instituto De Salud Carlos Iii
item COLTELL, OSCAR - Instituto De Salud Carlos Iii
item AROS, FERNANDO - Instituto De Salud Carlos Iii
item LAPETRA, JOSE - Instituto De Salud Carlos Iii
item SERRA-MAJEM, LLUIS - Instituto De Salud Carlos Iii
item RUIZ-GUTIERREZ, VALENTINA - Instituto De Salud Carlos Iii
item WARNBERG, JULIA - Instituto De Salud Carlos Iii
item FIOL, MIQUEL - Instituto De Salud Carlos Iii
item PINTO, XAVIER - Instituto De Salud Carlos Iii
item ORTEGA-AZORIN, CAROLINA - Instituto De Salud Carlos Iii
item MUNOZ, ANGEL - University Of Valencia
item MARTINEZ, J. ALFREDO - Instituto De Salud Carlos Iii
item GOMEZ-GARCIA, ENRIQUE - Instituto De Salud Carlos Iii
item GONZALEZ, JOSE - University Of Valencia
item ROS, EMILIO - Instituto De Salud Carlos Iii
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/17/2013
Publication Date: 11/1/2013
Citation: Corella, D., Carrasco, P., Sorlí, J.V., Estruch, R., Rico-Sanz, J., Martinez-Gonzalez, M., Salas-Salvado, J., Covas, M., Coltell, O., Aros, F., Lapetra, J., Serra-Majem, L., Ruiz-Gutierrez, V., Warnberg, J., Fiol, M., Pinto, X., Ortega-Azorin, C., Munoz, A., Martinez, J., Gomez-Garcia, E., Gonzalez, J.I., Ros, E., Ordovas, J.M. 2013. Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. Diabetes Care. 36:3803-3811.

Interpretive Summary: Cardiovascular disease (CVD) results from the complex interactions of genetic and environmental factors. We, and others, have shown that the genetic components predisposing one to CVD consists of hundreds of genes; thus the importance of understanding the role of each of those genes in the development of the disease in order to get a more complete picture of an individual’s risk. One of the genes implicated is known as Transcription factor 7-like 2 (TCF7L2). Polymorphisms (mutations) in this gene are strongly associated with type 2 diabetes, but the relationship with circulating fats in the blood and cardiovascular disease remains unknown. So too is the case for potential gene-diet interactions. Therefore, we investigated whether the associations between the TCF7L2-rs7903146 (C>T) polymorphism and type 2 diabetes, blood sugar, fats, and cardiovascular disease incidence were modulated by the consumption of a Mediterranean Diet (MedDiet). For this purpose, we utilized a randomized trial with 7,018 participants from the PREvención con DIetaMEDiterránea (PREDIMED) trial. Data were analyzed at baseline and after an average follow-up of 4.8 years. Our data demonstrate that the TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes. Moreover, MedDiet interacted significantly with rs7903146 on fasting blood sugar at baseline. When adherence to the MedDiet was low, homozygotes (carrying the same gene pattern on both sides of the chromosome) carrying the polymorphism (TT) had higher fasting blood sugar concentrations than those who were not homozygotes (CC+CT). Nevertheless, when adherence to the diet was high, this increase was not observed. This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides. Likewise, in the randomized trial, TT subjects had a higher incidence of stroke in the control group compared with CC, whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes. In summary, we show for the first time a gene-diet interaction modulating the risk of CVD. Our novel results suggest that a Mediterranean Diet may not only reduce increased fasting blood sugar and lipids in TT individuals, but also incidence of stroke.

Technical Abstract: Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIeta MEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62-2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 +/- 3.5 mg/dL) than CC+CT (127.3 +/- 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36-6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49-1.87]; P = 0.892 for TT compared with CC). Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence.