Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA

Xiaowei Hu, Jeongok G. Logan, Younghoon Kwon, Joao A.C. Lima, David R. Jacobs, Daniel Duprez, Lyndia Brumback, Kent D. Taylor, Peter Durda, W. Craig Johnson, Elaine Cornell, Xiuqing Guo, Yongmei Liu, Russell P. Tracy, Thomas W. Blackwell, George Papanicolaou, Gary F. Mitchell, Stephen S. Rich, Jerome I. Rotter, David J. Van Den BergJulio A. Chirinos, Timothy M. Hughes, Francine E. Garrett-Bakelman, Ani Manichaikul

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.

Original languageEnglish (US)
Article number17680
JournalScientific reports
Volume13
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • General

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