Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study

Sayols-Baixeras, S. ; Subirana, I. ; Lluis-Ganella, C. ; Civeira, F. (Universidad de Zaragoza) ; Roquer, J. ; Do, A.N. ; Absher, D. ; Cenarro, A. ; Munoz, D. ; Soriano-Tarraga, C. ; Jimenez-Conde, J. ; Ordovas, J.M. ; Senti, M. ; Aslibekyan, S. ; Marrugat, J. ; Arnett, D.K. ; Elosua, R.

Resumen: 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), HDLcholesterol (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.

Idioma: Inglés

DOI: 10.1093/hmg/ddw285

Año: 2016

Publicado en: HUMAN MOLECULAR GENETICS 25, 20 (2016), 4556-4565
ISSN: 0964-6906

Factor impacto JCR: 5.34 (2016)

Categ. JCR: GENETICS & HEREDITY rank: 23 / 166 = 0.139 (2016) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 46 / 287 = 0.16 (2016) - Q1 - T1

Factor impacto SCIMAGO: 3.698 - Genetics (Q1) - Molecular Biology (Q1) - Medicine (miscellaneous) (Q1) - Genetics (clinical) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/FIS92-0009-05
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/FIS93-0568
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/FIS96-0026-01
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/FIS99-0013-01
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI02-0471
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI05-1251
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI05-1297
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI08-1327
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI11-01801
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI12-00232
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI12-01238

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)