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- Lai, Chao-Qiang, et al.
(författare)
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Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A
- 2020
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Ingår i: American Journal of Clinical Nutrition. - : OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 112:5, s. 1200-1211
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitinc 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 GIroni 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 metaanalysis, 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 beta = 58.4 +/- 7.27, P = 8.98 x 10(-16) for CHO intake; beta = -36.4 +/- 5.95. P = 9.96 x 10(-10) for FAT intake; and beta = 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.
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| 2. |
- Prats-Uribe, Albert, et al.
(författare)
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High-density lipoprotein characteristics and coronary artery disease : a Mendelian randomization study
- 2020
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Ingår i: Metabolism. - : W B SAUNDERS CO-ELSEVIER INC. - 0026-0495 .- 1532-8600. ; 112
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDloGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSINI, n = 8372) and studied their relationship with CAD in the CARDloGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (beta = 027 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (beta = 0.29 (95%CI = 0.17; 0.40]), and triglyceride content in very large HDIs (beta = 0.14 [95%CI = 0.040; 025]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (beta = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDloGRAMplu5C4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not. (C) 2020 Elsevier Inc. All rights reserved.
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