Epigenome‐Wide Association Study for All‐Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 ( CASZ1 )

Abstract

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 ResultsCases 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 (P<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate–adjusted P<0.10: cg08215811 (SLC4A9; log2 fold change=−0.14); cg17845532 (MATK; fold change=−0.26); and cg17944110 (castor zinc finger 1 [CASZ1]; FC=0.26; P<0.0001; false discovery rate–adjusted P=0.046–0.080). Meta‐analysis identified 6 probes (false discovery rate–adjusted P<0.05): the 3 above, cg20428720 (intergenic), cg17647904 (NCOR2), and cg23198793 (CAPN3). Messenger RNA expression of 2 MATK isoforms was lower in cases (fold change=−0.24 [P=0.007] and fold change=−0.61 [P=0.009]). The CASZ1,NCOR2, and CAPN3 transcripts did not show differential expression (P>0.05); the SLC4A9 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, UBIAD1 (P=0.01) and CLSTN1 (P=0.03), were lower in cases.ConclusionsWe identified 6 novel methylation sites associated with all‐cause mortality. Methylation in CASZ1 may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.

DNA methylation signatures of incident coronary heart disease: findings from epigenome-wide association studies

“…ALPPL2 is another consistently replicated smokingmethylation locus, where the protein is a membranebinding glycosylated enzyme and is considered to be a highly specific tumour cell surface antigen [51]. DNA methylation of ALPPL2 has also been associated with all-cause mortality [52]. Furthermore, a recent EWAS of CHD identified signals in AHRR (cg05575921) and near ALPPL2 (cg21566642) to be associated with retrospective CHD with validation in independent iCHD samples [53].…”

The Association Between DNA&nbsp;Methylation of CASZ1&nbsp;Gene and Overweight/obesity in the Chinese Han Population

“…CASZ1 expression is essential for cardiomyocyte cell-cycle progression in the cardiovascular system [24]. A research has shown that CASZ1 gene was associated with BP [25], and methylation in CASZ1 may be associated with cardiovascular patients in regulating mortality [26]. It was widely known that BP is signi cantly associated with weight gain [18].…”

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

“…Here, we have set less threshold for |log FC| with the assumption that fold change depends on many factors like type of study performed, stage of disease at which sample was collected, methods used to perform the study, etc. Hence we assumed that the fold change in methylation profiling study might be far lower than that in the expression profiling study ( Maag et al, 2017 ; Raman et al, 2018 ; Abdulrahim et al, 2019 ; He et al, 2019 ; Yang et al, 2019 ).…”