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

Authors: SAYOLS-BAIXERAS, SERGI - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; SUBIRANA, ISAAC - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; LLUIS-GANELLA, CARLA - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; CIVEIRA, FERNANDO - INSTITUTO DE INVESTIGACION SANITARIA ARAGON; ROQUER, JAUME - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; DO, ANH - UNIVERSITY OF ALABAMA; ABSHER, DEVIN - HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY; CENARRO, ANA - INSTITUTO DE INVESTIGACION SANITARIA ARAGON; MUNOZ, DANIEL - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; SORIANO-TARRAGA, CAROLINA - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; JIMENEZ-CONDE, JORDI - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; SENTI, MARIANO - POMPEU FABRA UNIVERSITY; ASLIBEKYAN, STELLA - UNIVERSITY OF ALABAMA; MARRUGAT, JAUME - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE; ARNETT, DONNA - UNIVERSITY OF KENTUCKY; ELOSUA, ROBERTO - HOSPITAL DEL MAR MEDICAL RESEARCH INSTITUTE

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2016
Publication Date: 9/15/2016
Citation: Sayols-Baixeras, S., Subirana, I., Lluis-Ganella, C., Civeira, F., Roquer, J., Do, A., 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. 2016. Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study. Human Molecular Genetics. 25(20):4556-4565. doi: 10.1093/hmg/ddw285.

Interpretive Summary: Lipids circulating in the blood (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. There are many factors that determine their levels in the blood, including genetics and diet. More recently, DNA methylation has been investigated in this regard. DNA methylation is an inherited but also modifiable non-genetic mark that has been related to cardiovascular risk factors. Our aim was to identify regions in the genome showing differential DNA methylation related to serum lipid levels. For this purpose we performed a discovery study using the REGICOR Study (645 participants) that was followed by a validation of the significant findings in the Framingham Offspring Study (2,542 participants.) We identified fourteen differentially methylated sites located in nine genes and 2 regions between genes that showed differential methylation associated with lipid traits. These differentially methylated regions explained 0.7%, 9.5%, and 18.9% of the variability of total cholesterol, HDL cholesterol, and triglycerides in the Framingham Offspring Study. Further research is warranted to functionally validate these findings and assess the causality of these associations between differentially methylated loci and lipid metabolism.

Technical Abstract: 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.