DNA methylation and its relationship with lifestyle, environmental and cardiovascular risk factors
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Document Type
Document Version
Author
Director
Elosua Llanos, Roberto
Lluís Ganella, Carla
Lluís Ganella, Carla
Tutor
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Publication Date
Pages
167 p.
Embargo date
Citation
Sayols Baixeras, S. DNA methylation and its relationship with lifestyle, environmental and cardiovascular risk factors. Universitat Pompeu Fabra; 2019. handle: http://hdl.handle.net/10803/665398
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Citation
Doctoral program
Programa de doctorat en Biomedicina
Abstract
La malaltia cardiovascular, que és primera causa de mortalitat al món, com a fenotip complex depèn tant dels factors ambientals com dels genètics. Les variants genètiques comunes expliquen un 15-20% de l’heretabilitat de la malaltia. La metilació de l’ADN, que regula l’expressió gènica sense alterar la seqüència genètica primària, ha estat proposada com a mecanisme per unificar els efectes de l’estil de vida, els factors ambientals i els genètics. Per estudiar les relacions entre metilació de l’ADN i estil de vida, factors ambientals i factors de risc cardiovascular hem utilitzat estudis d’associació d’epigenoma complet, randomització mendeliana i integració d’òmiques. Hem inclòs dades de 10 estudis diferents, però els resultats han estat basats sobretot en l’estudi REGICOR (REgistre Gironí del COR). Aquesta tesi demostra l’associació entre 63 llocs de metilació (CpGs) i l’exposició al tabaquisme. No troba associació entre contaminació ambiental i metilació de l’ADN. Identifica 94 CpGs associats a obesitat i 14 als nivells lipídics. Observa que els nivells de triglicèrids en sang poden ser modificats i al mateix temps afectar la metilació en els gens CPT1A i SLC7A11, evidenciant la complexitat de l’homeostasis dels lípids. A més, s’ha realitzat el primer estudi que mostra l’associació entre la metilació de l’ADN i la funcionalitat de la HDL. Com a conclusions d’aquesta recerca destaquen la forta associació del tabac a un patró de metilació específic i l’associació entre la metilació de l’ADN i diferents factors de risc cardiovascular amb una relació causal complexa.
Coronary artery disease is the first cause of death worldwide, and as a complex disease implies the interplay between genetic and environmental factors. Common genetic variants explain only 15-20% of its heritability. DNA methylation, which regulates the gene expression without altering the DNA sequence, has been proposed as a heritable signature to explain this missing heritability and as a mediator effect of lifestyle and environment on health. To study the relationship between DNA methylation and smoking, air pollution, and cardiovascular risk factors (obesity, lipid profile, and HDL functionality) we used epigenome-wide association studies, Mendelian randomization, and multi-stage omics integration approaches. We included data from ten studies, but the results were mainly based on the REGICOR (REgistre GIroní del COR) cohort. We report the association between smoking and 63 methylation sites (CpGs). We did not find association between air pollution and DNA methylation. We identified 94 CpGs associated with obesity and 14 with lipid profile. We observed that methylation at CPT1A and SLC7A11 can modify or be affected by the triglycerides levels, highlighting the complexity of the lipids homeostasis. Finally, we performed the first study showing an association between DNA methylation and HDL functionality. As conclusions of this research, smoking is strongly associated with a distinctive methylation pattern and there is a relationship between DNA methylation and several cardiovascular risk factors, although its causality is complex.
Coronary artery disease is the first cause of death worldwide, and as a complex disease implies the interplay between genetic and environmental factors. Common genetic variants explain only 15-20% of its heritability. DNA methylation, which regulates the gene expression without altering the DNA sequence, has been proposed as a heritable signature to explain this missing heritability and as a mediator effect of lifestyle and environment on health. To study the relationship between DNA methylation and smoking, air pollution, and cardiovascular risk factors (obesity, lipid profile, and HDL functionality) we used epigenome-wide association studies, Mendelian randomization, and multi-stage omics integration approaches. We included data from ten studies, but the results were mainly based on the REGICOR (REgistre GIroní del COR) cohort. We report the association between smoking and 63 methylation sites (CpGs). We did not find association between air pollution and DNA methylation. We identified 94 CpGs associated with obesity and 14 with lipid profile. We observed that methylation at CPT1A and SLC7A11 can modify or be affected by the triglycerides levels, highlighting the complexity of the lipids homeostasis. Finally, we performed the first study showing an association between DNA methylation and HDL functionality. As conclusions of this research, smoking is strongly associated with a distinctive methylation pattern and there is a relationship between DNA methylation and several cardiovascular risk factors, although its causality is complex.
Keywords
Epigenetics, DNA methylation, Cardiovascular risk factors, Mendelian randomization, Epigenètica, Metilació de l'ADN, Factors de risc cardiovascular, Factors ambientals, Randomització mendeliana
Subjects
616.1 - Pathology of the circulatory system, blood vessels. Cardiovascular disorders
Publisher
Universitat Pompeu Fabra
