An 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
Background—A variant (rs3812316, C771G, 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.
Methods and Results—We studied 7,166 participants in the 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. Data were analyzed at baseline and longitudinally. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) for cardiovascular outcomes. The MLXIPL-rs3812316 was associated with lower baseline triglycerides (P=5.5x10-5) and lower hypertriglyceridemia (odds ratio [OR]: 0.73; 95%CI, 0.63-0.85; P=1.4x10-6 in G-carriers versus CC). This association was modulated by baseline adherence to MedDiet (AdMedDiet). When AdMedDiet was high, the protection was stronger (OR: 0.63, 95%CI: 0.51-0.77; P=8.6x10-6) than when AdMedDiet was low (OR: 0.88, 95%CI: 0.70-1.09;P=0.219). Throughout the follow-up, both the MLXIPL-rs3812316 (P=3.8x10-6) 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 (HR: 0.34; 95%CI: 0.12-0.93;P=0.036 and 0.90; 95%CI: 0.35-2.33;P=0.830, respectively).
Conclusions—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.
Clinical Trial Registration—www.controlled-trials.com; Unique Identifier: ISRCTN35739639.
- Mediterranean diet
- candidate genes
- cardiovascular disease prevention
- cardiovascular events
- cardiovascular genomics
- Received April 15, 2013.
- Revision received December 26, 2013.
- Accepted January 8, 2014.