Dissecting the association of autophagy-related genes with cardiovascular diseases and intermediate vascular traits: A population-based approach

• Published in: PloS one Vol. 14; no. 3; p. e0214137
• Main Authors: Portilla-Fernandez, Eliana, Ghanbari, Mohsen, van Meurs, Joyce B J, Danser, A H Jan, Franco, Oscar H, Muka, Taulant, Roks, Anton, Dehghan, Abbas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.03.2019; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Analysis; Association analysis; Autophagy; Autophagy (Cytology); Autophagy-Related Protein 7 - genetics; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Proteins - genetics; Biology and Life Sciences; Blood lipids; Blood pressure; Blood pressure regulation; Cardiovascular disease; Cardiovascular diseases; Cell death; Cholesterol; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Coronary heart disease; CpG Islands; Cysteine Endopeptidases - genetics; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); DNA; DNA Methylation; DNA sequencing; EDTA; Epidemiology; Epigenetics; Exome Sequencing; Fasting; Female; Gene sequencing; Genes; Genetic analysis; Genetic aspects; Genetic diversity; Genetic polymorphisms; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Glucose; Glucose metabolism; Health; Heart diseases; High density lipoprotein; Homeostasis; Humans; Hypertension; Insulin; Internal medicine; Intracellular Signaling Peptides and Proteins - genetics; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Low density lipoprotein; Low density lipoproteins; Male; Medicine and Health Sciences; Metabolism; Methylation; Microtubule-Associated Proteins - genetics; Phagocytosis; Pharmacology; Polymorphism; Polymorphism, Single Nucleotide; Population; Preventive medicine; Quantitative Trait, Heritable; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Triglycerides; Type 2 diabetes; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0214137

Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.