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

Publication ,  Journal Article
Abdulrahim, JW; Kwee, LC; Grass, E; Siegler, IC; Williams, R; Karra, R; Kraus, WE; Gregory, SG; Shah, SH
Published in: J Am Heart Assoc
November 5, 2019

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 (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. Conclusions We 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.

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Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

November 5, 2019

Volume

8

Issue

21

Start / End Page

e013228

Location

England

Related Subject Headings

  • Transcription Factors
  • RNA, Messenger
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Isoforms
  • Nuclear Receptor Co-Repressor 2
  • Muscle Proteins
  • Male
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Profiling
 

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Abdulrahim, J. W., Kwee, L. C., Grass, E., Siegler, I. C., Williams, R., Karra, R., … Shah, S. H. (2019). Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1). J Am Heart Assoc, 8(21), e013228. https://doi.org/10.1161/JAHA.119.013228
Abdulrahim, Jawan W., Lydia Coulter Kwee, Elizabeth Grass, Ilene C. Siegler, Redford Williams, Ravi Karra, William E. Kraus, Simon G. Gregory, and Svati H. Shah. “Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1).J Am Heart Assoc 8, no. 21 (November 5, 2019): e013228. https://doi.org/10.1161/JAHA.119.013228.
Abdulrahim JW, Kwee LC, Grass E, Siegler IC, Williams R, Karra R, et al. Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1). J Am Heart Assoc. 2019 Nov 5;8(21):e013228.
Abdulrahim, Jawan W., et al. “Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1).J Am Heart Assoc, vol. 8, no. 21, Nov. 2019, p. e013228. Pubmed, doi:10.1161/JAHA.119.013228.
Abdulrahim JW, Kwee LC, Grass E, Siegler IC, Williams R, Karra R, Kraus WE, Gregory SG, Shah SH. Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1). J Am Heart Assoc. 2019 Nov 5;8(21):e013228.
Journal cover image

Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

November 5, 2019

Volume

8

Issue

21

Start / End Page

e013228

Location

England

Related Subject Headings

  • Transcription Factors
  • RNA, Messenger
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Isoforms
  • Nuclear Receptor Co-Repressor 2
  • Muscle Proteins
  • Male
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Profiling