Amino Acid Change in the Carbohydrate Response Element Binding Protein is associated with lower triglycerides and myocardial infarction incidence depending on level of adherence to the Mediterranean diet in the PREDIMED trial

Authors: ORTEGA-AZORÍN, CAROLINA - University Of Valencia; SORLÍ, JOSE - University Of Valencia; ESTRUCH, RAMÓN - University Of Valencia; ASENSIO, EVA - University Of Valencia; COLTELL, OSCAR - University Of Valencia; GONZALEZ, JOSE - University Of Valencia; MARTINEZ-GONZALEZ, MIGUEL ANGEL - University Of Valencia; ROS, EMILIO - University Of Valencia; SALAS-SALVADO, JORDI - University Of Valencia; FITO, MONTSERRAT - University Of Valencia; AROS, FERNANDO - University Of Valencia; LAPETRA, JOSE - University Of Valencia; SERRA-MAJEM, LLUIS - University Of Valencia; RUIZ-GUTIERREZ, VALENTINA - University Of Valencia; GOMEZ-GARCIA, ENRIQUE - University Of Valencia; FIOL, MIQUEL - University Of Valencia; FLORES, GEMMA - University Of Valencia; PINTO, XAVIER - University Of Valencia; SAIZ, CARMEN - University Of Valencia; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CORELLA, DELORES - University Of Valencia

Submitted to: Circulation: Cardiovascular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2014
Publication Date: 2/1/2014
Citation: Ortega-Azorín, C., Sorlí, J.V., Estruch, R., Asensio, E.M., Coltell, O., Gonzalez, J.I., Martinez-Gonzalez, M., Ros, E., Salas-Salvado, J., Fito, M., Aros, F., Lapetra, J., Serra-Majem, L., Ruiz-Gutierrez, V., Gomez-Garcia, E., Fiol, M., Flores, G., Pinto, X., Saiz, C., Ordovas, J.M., Corella, D. 2014. Amino Acid Change in the Carbohydrate Response Element Binding Protein is associated with lower triglycerides and myocardial infarction incidence depending on level of adherence to the Mediterranean diet in the PREDIMED trial. Circulation: Cardiovascular Genetics. 7(1):49-58. DOI:10.1161/CIRCGENETICS.113.000301.

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 these genes is known as MLXIPL (Max-like protein X interacting protein-like) and encodes the carbohydrate response element binding protein. A variant of this gene (Gln241His) has been associated with lower triglycerides, suggesting a protective role against CVD. However, its association with CVD and the potential presence of gene-diet interactions modulating these traits are unknown. Therefore, in order to answer these questions, we studied 7166 participants in the PREvención with DIeta MEDiterránea (PREDIMED) trial testing a Mediterranean diet (MedDiet) intervention versus a control diet for cardiovascular prevention, with a median follow-up of 4.8 years. Diet, lipids, MLXIPL polymorphisms, and cardiovascular events were assessed. Our data shows that the MLXIPL-Gln241His was associated with lower baseline triglycerides and lower hypertriglyceridemia. Moreover, this association was modulated by initial adherence to a MedDiet when the participants joined the study. When adherence to MedDiet was high, the protection was stronger than when adherence to MedDiet was low. Throughout the approximately 5-years of follow-up, both the MLXIPL- Gln241His and the MedDiet intervention were significantly associated with decreased triglycerides. Likewise in carriers of the genetic variant, MedDiet intervention was associated with greater total CVD reduction and specifically for myocardial infarction. In summary, these novel findings demonstrate that MedDiet enhances the triglyceride-lowering effect of the MLXIPL- Gln241His variant and strengthens its protective effect on heart attack incidence.

Technical Abstract: A variant (rs3812316, C771G, and Gln241His) in the MLXIPL (Max-like protein X interacting protein-like) gene encoding the carbohydrate response element binding protein has been associated with lower triglycerides. However, its association with cardiovascular diseases and gene-diet interactions modulating these traits are unknown. We studied 7166 participants in the PREvención with DIeta MEDiterránea trial testing a Mediterranean diet (MedDiet) intervention versus a control diet for cardiovascular prevention, with a median follow-up of 4.8 years. Diet, lipids, MLXIPL polymorphisms, and cardiovascular events were assessed. Data were analyzed at baseline and longitudinally. We used multivariable-adjusted Cox regression to estimate hazard ratios for cardiovascular outcomes. The MLXIPL-rs3812316 was associated with lower baseline triglycerides (P=5.5×10**-5) and lower hypertriglyceridemia (odds ratio, 0.73; 95% confidence interval [CI], 0.63-0.85; P=1.4×10**-6 in G-carriers versus CC). This association was modulated by baseline adherence to MedDiet. When adherence to MedDiet was high, the protection was stronger (odds ratio, 0.63; 95% CI, 0.51-0.77; P=8.6×10**-6) than when adherence to MedDiet was low (odds ratio, 0.88; 95% CI, 0.70-1.09; P=0.219). Throughout the follow-up, both the MLXIPL-rs3812316 (P=3.8×10**-6) and the MedDiet intervention (P=0.030) were significantly associated with decreased triglycerides. Likewise in G-carriers MedDiet intervention was associated with greater total cardiovascular risk reduction and specifically for myocardial infarction. In the MedDiet, but not in the control group, we observed lower myocardial infarction incidence in G-carriers versus CC (hazard ratios, 0.34; 95% CI, 0.12-0.93; P=0.036 and 0.90; 95% CI, 0.35-2.33; P=0.830, respectively). Our novel results suggest that MedDiet enhances the triglyceride-lowering effect of the MLXIPL-rs3812316 variant and strengthens its protective effect on myocardial infarction incidence.