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

• Original Article

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

1. Carolina Ortega-Azorín1, 
2. Jose V. Sorlí1, 
3. Ramón Estruch2,
4. Eva M. Asensio1, 
5. Oscar Coltell3, 
6. José I. González1,
7. Miguel Ángel Martínez-González4, 
8. Emilio Ros5, 
9. Jordi Salas-Salvadó6, 
10. Montserrat Fitó7, 
11. Fernando Arós8, 
12. José Lapetra9, 
13. Lluís Serra-Majem10, 
14. Valentina Ruiz-Gutiérrez11, 
15. Enrique Gómez-Gracia12, 
16. Miquel Fiol13, 
17. Gemma Flores14, 
18. Xavier Pintó15, 
19. Carmen Saiz16, 
20. José M. Ordovás17 and 
21. Dolores Corella1*

+Author Affiliations

1. ¹Department of Preventive Medicine, School of Medicine, Valencia University, Valencia & CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
2. ²CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Internal Medicine, IDIBAPS, Hospital Clinic, Barcelona, Spain
3. ³CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Computer Languages and Systems, Jaume I University, Castellón, Spain
4. ⁴CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain
5. ⁵CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Lipid Clinic, Endocrinology and Nutrition Service, IDIBAPS, Hospital Clinic, Barcelona, Spain
6. ⁶CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Human Nutrition Unit, Faculty of Medicine, University Rovira i Virgili, Reus, Spain
7. ⁷CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Cardiovascular Risk and Nutrition Research Group, Hospital del Mar d'Investigació Mèdica, Barcelona, Spain
8. ⁸CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Cardiology, Hospital Txagorritxu, Vitoria, Spain
9. ⁹CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Family Medicine, San Pablo Health Center, Sevilla, Spain
10. ¹⁰CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Clinical Sciences, Las Palmas de Gran Canaria University, Las Palmas de Gran Canaria, Spain
11. ¹¹CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Instituto de la Grasa, Consejo Superior de Investigaciones Científicas, Sevilla, Spain
12. ¹²CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Department of Epidemiology, School of Medicine, Malaga University, Málaga, Spain
13. ¹³CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & University Institute for Health Sciences, Hospital Son Dureta, Palma de Mallorca, Spain
14. ¹⁴Primary Care Division, Catalan Institute of Health, Barcelona, Spain
15. ¹⁵CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III (ISCIII), Madrid & Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
16. ¹⁶Department of Preventive Medicine, School of Medicine, Valencia University, Valencia, Spain
17. ¹⁷Department of Cardiovascular Epidemiology and Population Genetics, CNIC & IMDEA Alimentación, Madrid, Spain & Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging-Tufts University, Boston, MA

1. ↵* Genetic and Molecular Epidemiology Unit, Valencia University Blasco Ibañez, 15, 46010-Valencia, Spain dolores.corella@uv.es

Abstract

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. TheMLXIPL-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 theMLXIPL-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.

Key Words:

• nutrition
• Mediterranean diet
• nutrigenetics
• candidate genes
• cardiovascular disease prevention
• cardiovascular events
• cardiovascular genomics
• diet

• Received April 15, 2013.
• Revision received December 26, 2013.
• Accepted January 8, 2014.