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

Abstract

G iven that hypertriglyceridemia is re-emerging as an important cardiovascular disease risk factor, [1][2][3] it is essential to gain further understanding about the genes involved and the environmental factors that modulate their expression. 4,5 Outstanding among the genes that have been associated recently with triglyceride metabolism is the MLXIPL (Max-like protein X interacting protein-like, also known as Mondo B) that encodes the carbohydrate response element binding protein (ChREBP). In a genome-wide association study, 6 we and others reported for the first time that the MLXIPL was a new locus associated with plasma triglycerides. We found that the minor allele of the intergenic rs17145738 polymorphism, located downstream of MLXIPL, was associated with significantly lower plasma triglyceride concentrations.6 This observation was in line with previous work in animal models in which the ChREBP, discovered by the group of Uyeda and Repa, 7 was characterized as an important transcription factor coupling hepatic glucose utilization Background-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. Methods and Results-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 ) 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, P=0.036 and 0.90; 95% CI, 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.

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

“…As discussed earlier, there are published reports of genetic variants that interact with dietary composition to modulate biomarkers and health outcomes, including within the context of randomized trials. 57,300 However, most have not been validated through prospective, genotype-guided, randomized, controlled dietary intervention trials. Historical limitations in nutrition research limited the ability to develop clear evidence-based guidelines; personalized nutrition presents an opportunity to greatly improve on these recommendations using current standards and technologies.…”

miR‐1322 regulates ChREBP expression via binding a 3′‐UTR variant (rs1051943)

“…Many single‐nucleotide polymorphisms (SNPs) in or near the ChREBP gene have been found to be associated with plasma triglyceride levels by genome‐wide association studies (GWASs) . During the last decade, more than 20 studies confirmed the association between ChREBP gene variations and plasma triglyceride levels, as well as the association with coronary artery disease (CAD) …”

The regulation and role of carbohydrate response element‐binding protein in metabolic homeostasis and disease

“…Carbohydrate response element‐binding protein has a clear role in regulating hepatic steatosis; however, its effect on insulin resistance and its role in obesity, diabetes and other metabolic diseases is not as clear. Genome‐wide scans have revealed that variants in MLXIPL are associated with plasma triglycerides, and gene polymorphisms are associated with coronary artery disease in a Chinese population . Furthermore, a study investigating the effectiveness of Mediterranean diet on reducing cardiovascular disease, found that an MLXIPL variant was associated with a lowered risk and that there was a stronger protection with diet combined with the variant than either factor alone .…”