Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 ().

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome-wide association study (EWAS) for all-cause mortality with whole-transcriptome data in a cardiovascular cohort (CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow-up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δβ). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated (<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate-adjusted <0.10: cg08215811 (; log fold change=-0.14); cg17845532 (; fold change=-0.26); and cg17944110 (castor zinc finger 1 []; FC=0.26; <0.0001; false discovery rate-adjusted =0.046-0.080). Meta-analysis identified 6 probes (false discovery rate-adjusted <0.05): the 3 above, cg20428720 (intergenic), cg17647904 (), and cg23198793 (). Messenger RNA expression of 2 isoforms was lower in cases (fold change=-0.24 [=0.007] and fold change=-0.61 [=0.009]). The , , and transcripts did not show differential expression (>0.05); the transcript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element, (=0.01) and (=0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all-cause mortality. Methylation in may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.