Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A

Authors: Lai, Chao Qiang; Parnell, Laurence; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GUO, TAO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SAYOLS-BAIXERAS, SERGI - Hospital Del Mar Medical Research Institute; ASLIBEKYAN, STELLA - University Of Alabama At Birmingham; TIWARI, HEMANT - University Of Alabama At Birmingham; IRVIN, MARGUERITE - University Of Alabama At Birmingham; BENDER, CARL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FEI, DAVID - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HIDALGO, BERTHA - University Of Alabama At Birmingham; HOPKINS, PAUL - University Of Utah; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology; PROVINCE, MICHAEL - Washington University; ELOSUA, ROBERTO - Hospital Del Mar Medical Research Institute; ARNETT, DONNA - University Of Kentucky; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/22/2020
Publication Date: 9/15/2020
Citation: Lai, C., Parnell, L.D., Smith, C.E., Guo, T., Sayols-Baixeras, S., Aslibekyan, S., Tiwari, H.K., Irvin, M.R., Bender, C., Fei, D., Hidalgo, B., Hopkins, P., Absher, D.M., Province, M., Elosua, R., Arnett, D.K., Ordovas, J.M. 2020. Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A. American Journal of Clinical Nutrition. 112(5):1200–1211. https://doi.org/10.1093/ajcn/nqaa233.
DOI: https://doi.org/10.1093/ajcn/nqaa233

Interpretive Summary: Dietary habits can modify epigenetic status without changing genetic code, affecting the risk of metabolic diseases. Although recent studies have shown that a high epigenetic signal at the CPT1A gene is consistently associated with reduced risk of metabolic diseases (conditions like high triglycerides, obesity, type 2 diabetes, hypertension, metabolic syndrome), the mechanism by which this happens is unknown. In this study, by examining three different populations around the world, we found that total amount of carbohydrates in the diet and the ratio of total carbohydrate intake to total fat intake associated with more of this epigenetic signal. In contrast, total fat intake correlated with less of this epigenetic signal. Looking deeper, we found evidence that the increased epigenetic signal at CPT1A from carbohydrate intake can lower the risk of metabolic diseases. Conversely, a decreased epigenetic signal at CPT1A by fat intake can raise the risk of these diseases. Our study on CPT1A implies the extent to which the balance between macronutrients of carbohydrate and fat diet can influence the regulation of gene activity, and that such communication between diet and genome can have health consequences.

Technical Abstract: Objective: Dietary habits can modify epigenetic status that affects the risk of metabolic diseases. Recent epigenome-wide association studies identified cg00574958 DNA methylation at CPT1A, associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism that underlies these associations is unknown. Design: We examined associations between total carbohydrate (CHO) and total fat (FAT) intake, as percentages of total energy intake, and the CHO/FAT ratio with methylation site CPT1A-cg00574958, and the risk of metabolic diseases in three populations (Genetics of Lipid Lowering Drugs and Diet Network, n=978; Framingham Heart Study, n=2331; REgistre GIroni del COR study, n=645) while adjusting for potential confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. Results: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all three populations. Our results showed that CHO intake and the CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation with beta=58.4, P=8.98E-16 for CHO intake, beta=-36.4 and P=9.96E-10 for FAT intake, and beta=3.30 and P=1.48E-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence, reducing the risk of metabolic diseases, whereas FAT intake, inhibits CPT1A methylation, increasing the risk of metabolic diseases. Conclusions: Our results strongly support that the proportion of total energy supplied by CHO and FAT has a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.