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Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor α

Research output: Contribution to journalArticle

  • Stella Aslibekyan
  • Golareh Agha
  • Elena Colicino
  • Anh N. Do
  • Jari Lahti
  • Symen Ligthart
  • Carola Marzi
  • Michael M Mendelson
  • Toshiko Tanaka
  • Matthias Wielscher
  • Devin M Absher
  • Luigi Ferrucci
  • Oscar H. Franco
  • Christian Gieger
  • Harald Grallert
  • Dena Hernandez
  • Tianxiao Huan
  • Stella Iurato
  • Roby Joehanes
  • Allan C Just
  • Sonja Kunze
  • Honghuang Lin
  • Chunyu Liu
  • James B. Meigs
  • Joyce B. J. vVan Meurs
  • Ann Zenobia Moore
  • Annette Peters
  • Katri Räikkönen
  • Wolfgang Rathmann
  • Michael Roden
  • Katharina Schramm
  • Joel D. Schwartz
  • André G Uitterlinden
  • Pantel Vokonas
  • Melanie Waldenberger
  • Chen Yao
  • Degui Zhi
  • Andrea A Baccarelli
  • Stefania Bandinelli
  • Abbas Dehghan
  • Johan Eriksson
  • Christian Herder
  • Marjo-Riitta Järvelin
  • Daniel Levy
  • Donna K Arnett

Related Edinburgh Organisations

Original languageEnglish
JournalJAMA cardiology
Early online date4 Apr 2018
DOIs
Publication statusE-pub ahead of print - 4 Apr 2018

Abstract

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision.

Objective : To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings.

Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events.

Exposures: Circulating TNF-α concentration.

Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease.

Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = −0.01 [0.003]; P = 7.36 × 10−8), cg08122652 (β [SE] = −0.008 [0.002]; P = 2.24 × 10−7), and cg22930808(β [SE] = −0.01 [0.002]; P = 6.92 × 10−8); NLRC5 at cg16411857 (β [SE] = −0.01 [0.002]; P = 2.14 × 10−13) and cg07839457 (β [SE] = −0.02 [0.003]; P = 6.31 × 10−10); or ABO, at cg13683939 (β [SE] = 0.04 [0.008]; P = 1.42 × 10−7) and cg24267699 (β [SE] = −0.009 [0.002]; P = 1.67 × 10−7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α–linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10−5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10−5).

Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

ID: 58031279