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-densityand high-density lipoproteincholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is an inherited but also modifiable epigenetic mark that has been related tocardiovascular 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 HumanMethylation450 BeadChip. Atwo-stage epigenome-wide association study was performed, with a discovery sample intheREGICOR study (n=645)and validation in the Framingham Offspring Study (n=2,542).FourteenCpG sites located in 9 genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP andSLC7A11) and 2 intergenic regions showeddifferential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation relatedto total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP andSLC7A11).These CpGs explained0.7%, 9.5% and18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genesSREBF2and SREBF1was 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, SREBF1expression wasdirectly associated with HDL cholesterol(p-value=0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1and CPT1Awerealso associated with lipid profile. Further research is warranted to functionally validatethesenew loci and assess the causality ofnew and established associationsbetween these differentially methylated lociand lipid metabolism.This work was supported by the following sources: Agència de Gestio Ajuts Universitaris de Recerca [2014 SGR 240]; the Spanish Ministry of Economy through the Carlos III Health Institute [ISCIII-FIS-FEDER-ERDF PI12-00232, PI12-01238, PI11-01801, PI08-1327, PI05-1251, PI05-1297, PI02-0471, FIS99/0013-01, FIS96/0026-01, FIS93/0568, FIS92/0009-05], and the Red de Investigacion Cardiovascular [RD12/0042/0013, RD12/0042/0020, RD12/0042/0055, RD12/0042/0061]. S.S-B. was funded by a contract from Instituto de Salud Carlos III FEDER [IFI14/00007] and Daniel Bravo Andreu Private Foundation. GOLDN: The GOLDN study (AND, DA, JO, SA, DKA) was funded by the US National Institute of Health (NIH)/National Heart, Lung and Blood Institutes (http://www.nhlbi.nih.gov) grants R01HL104135 and U01HL72524

Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual’s lifetime. Telomere shortening is a hallmark of molecular aging and is associated with premature appearance of diseases associated with aging. Here, we discuss the role of telomere shortening as a direct cause for aging and age-related diseases. In particular, we draw attention to the fact that telomere length influences longevity. Furthermore, we discuss intrinsic and environmental factors that can impact on human telomere erosion. Finally, we highlight recent advances in telomerase-based therapeutic strategies for the treatment of diseases associated with extremely short telomeres owing to mutations in telomerase, as well as age-related diseases, and ultimately aging itself