Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.
Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain
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Sayols-Baixeras
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.|CIBER Epidemiology and Public Health, Barcelona, Catalonia, Spain
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Subirana
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.
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Lluis-Ganella
Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
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Civeira
Department of Neurology, Neurovascular Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Catalonia, Spain.
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Roquer
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
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Absher
Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain.
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Cenarro
Cardiovascular Risk and Nutrition Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.
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Muñoz
Department of Neurology, Neurovascular Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Catalonia, Spain.
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Soriano-Tárraga
Department of Neurology, Neurovascular Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Catalonia, Spain.
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Jiménez-Conde
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
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Ordovas
Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Catalonia, Spain.
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Senti
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Aslibekyan
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.
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Marrugat
Dean's Office, College of Public Health, University of Kentucky, Lexington, KY, USA.
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Arnett
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Catalonia, Spain.
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Elosua
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism
C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D027182:Amino Acid Transport System y+; D002352:Carrier Proteins; C118895:SLC7A11 protein, human; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C484739:SYNGAP1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; C486715:TXNIP protein, human; D014280:Triglycerides; D020703:ras GTPase-Activating Proteins; D002784:Cholesterol; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases; C497128:PHOSPHO1 protein, human; D010744:Phosphoric Monoester Hydrolases