Epigenome-wide association study of total nicotine equivalents in multiethnic current smokers from three prospective cohorts

Brian Z. Huang, Alexandra M. Binder, Brandon Quon, Yesha M. Patel, Annette Lum-Jones, Maarit Tiirikainen, Sharon E. Murphy, Lenora Loo, Alika K. Maunakea, Christopher A. Haiman, Lynne R. Wilkens, Woon Puay Koh, Qiuyin Cai, Melinda C. Aldrich, Kimberly D. Siegmund, Stephen S. Hecht, Jian Min Yuan, William J. Blot, Daniel O. Stram, Loïc Le MarchandSungshim L. Park

Research output: Contribution to journalArticlepeer-review

Abstract

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10−8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10−4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%–44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.

Original languageEnglish (US)
Pages (from-to)456-472
Number of pages17
JournalAmerican Journal of Human Genetics
Volume111
Issue number3
DOIs
StatePublished - Mar 7 2024

Bibliographical note

Publisher Copyright:
© 2024 American Society of Human Genetics

Keywords

  • cohort
  • DNA methylation
  • epigenetics
  • epigenome-wide association study
  • EWAS
  • lung cancer
  • nicotine
  • race and ethnicity
  • smoking
  • total nicotine equivalents

PubMed: MeSH publication types

  • Journal Article

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