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

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ABSTRACT

Background

Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown.

Objectives

We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases.

Methods

We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for 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 3 populations. Our results showed that CHO intake and 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 β = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; β = −36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated 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, thereby increasing the risk of metabolic diseases.

Conclusions

Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.

Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)—NCT01023750; and the Framingham Heart Study (FHS)—NCT00005121.

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Most cited references 27

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DNA methylation age of blood predicts all-cause mortality in later life

Riccardo E Marioni, Sonia Shah, Allan McRae … (2015)

Background DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Results Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. Conclusions DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.

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Identifiability and Exchangeability for Direct and Indirect Effects

Sander Greenland, James M. Robins (1992)

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Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis

Sara B Seidelmann, Brian Claggett, Susan Cheng … (2018)

Summary Background Low carbohydrate diets, which restrict carbohydrate in favour of increased protein or fat intake, or both, are a popular weight-loss strategy. However, the long-term effect of carbohydrate restriction on mortality is controversial and could depend on whether dietary carbohydrate is replaced by plant-based or animal-based fat and protein. We aimed to investigate the association between carbohydrate intake and mortality. Methods We studied 15 428 adults aged 45–64 years, in four US communities, who completed a dietary questionnaire at enrolment in the Atherosclerosis Risk in Communities (ARIC) study (between 1987 and 1989), and who did not report extreme caloric intake ( 4200 kcal per day for men and 3600 kcal per day for women). The primary outcome was all-cause mortality. We investigated the association between the percentage of energy from carbohydrate intake and all-cause mortality, accounting for possible non-linear relationships in this cohort. We further examined this association, combining ARIC data with data for carbohydrate intake reported from seven multinational prospective studies in a meta-analysis. Finally, we assessed whether the substitution of animal or plant sources of fat and protein for carbohydrate affected mortality. Findings During a median follow-up of 25 years there were 6283 deaths in the ARIC cohort, and there were 40 181 deaths across all cohort studies. In the ARIC cohort, after multivariable adjustment, there was a U-shaped association between the percentage of energy consumed from carbohydrate (mean 48·9%, SD 9·4) and mortality: a percentage of 50–55% energy from carbohydrate was associated with the lowest risk of mortality. In the meta-analysis of all cohorts (432 179 participants), both low carbohydrate consumption ( 70%) conferred greater mortality risk than did moderate intake, which was consistent with a U-shaped association (pooled hazard ratio 1·20, 95% CI 1·09–1·32 for low carbohydrate consumption; 1·23, 1·11–1·36 for high carbohydrate consumption). However, results varied by the source of macronutrients: mortality increased when carbohydrates were exchanged for animal-derived fat or protein (1·18, 1·08–1·29) and mortality decreased when the substitutions were plant-based (0·82, 0·78–0·87). Interpretation Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50–55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality.

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Author and article information

Contributors

Laurence D Parnell: (View ORCID Profile)

Caren E Smith: (View ORCID Profile)

Sergi Sayols-Baixeras: (View ORCID Profile)

Jose M Ordovas: (View ORCID Profile)

Journal

Title: The American Journal of Clinical Nutrition

Publisher: Oxford University Press (OUP)

ISSN (Print): 0002-9165

ISSN (Electronic): 1938-3207

Publication date Created: September 15 2020

Publication date (Electronic): September 15 2020

Affiliations

[1 ]USDA Agricultural Research Service, Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

[2 ]Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

[3 ]Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain

[4 ]CIBER Cardiovascular Diseases (CIBERCV), Barcelona, Catalonia, Spain

[5 ]Molecular Epidemiology, Department of Medical Sciences, Uppsala Universitet, Uppsala, Sweden

[6 ]Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL, USA

[7 ]Department of Cardiovascular Genetics, University of Utah, Salt Lake City, UT, USA

[8 ]Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA

[9 ]Department of Genetics, Washington University School of Medicine, St Louis, MO, USA

[10 ]College of Public Health, University of Kentucky, Lexington, KY, USA

[11 ]IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain

[12 ]Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Article

DOI: 10.1093/ajcn/nqaa233

PMC ID: 7657341

PubMed ID: 32930325

SO-VID: 26da35f4-dcc6-4991-921c-5d499eeda155

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

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ABSTRACT

Background

Objectives

Methods

Results

Conclusions

Related collections

Genes & Diseases

Most cited references 27

DNA methylation age of blood predicts all-cause mortality in later life

Identifiability and Exchangeability for Direct and Indirect Effects

Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis

Author and article information

Contributors

Journal

Affiliations

Article

History

Comments

Comment on this article

Similar content 225

Cited by 24

Most referenced authors 576