Genome-wide association study of susceptibility to particulate matter–associated QT prolongation

Rahul Gondalia, Christy L. Avery, Melanie D. Napier, Raúl Méndez-Giráldez, James D. Stewart, Colleen M. Sitlani, Yun Li, Kirk C. Wilhelmsen, Qing Duan, Jeffrey Roach, Kari E. North, Alexander P. Reiner, Zhu Ming Zhang, Lesley F. Tinker, Jeff D. Yanosky, Duanping Liao, Eric A. Whitsel

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

BACKGROUND: Ambient particulate matter (PM) air pollution exposure has been associated with increases in QT interval duration (QT). However, innate susceptibility to PM-associated QT prolongation has not been characterized. OBJECTIVE: To characterize genetic susceptibility to PM-associated QT prolongation in a multi-racial/ethnic, genome-wide association study (GWAS). METHODS: Using repeated electrocardiograms (1986–2004), longitudinal data on PM <10 μm in diameter (PM10), and generalized estimating equations methods adapted for low-prevalence exposure, we estimated approximately 2:5 ×106 SNP × PM10 interactions among nine Women’s Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (n = 22,158), then combined subpopulation-specific results in a fixed-effects, inverse variance-weighted meta-analysis. RESULTS: A common variant (rs1619661; coded allele: T) significantly modified the QT-PM10 association (p =2:11 × 10− 8). At PM10 concentrations >90th percentile, QT increased 7 ms across the CC and TT genotypes: 397 (95% confidence interval: 396, 399) to 404 (403, 404) ms. However, QT changed minimally across rs1619661 genotypes at lower PM10 concentrations. The rs1619661 variant is on chromosome 10, 132 kilobase (kb) downstream from CXCL12, which encodes a chemokine, stromal cell-derived factor 1, that is expressed in cardiomyocytes and decreases calcium influx across the L-type Ca2+ channel. CONCLUSIONS: The findings suggest that biologically plausible genetic factors may alter susceptibility to PM10 -associated QT prolongation in populations protected by the U.S. Environmental Protection Agency’s National Ambient Air Quality Standards. Independent replication and functional characterization are necessary to validate our findings.

Original languageEnglish (US)
Article number067002
JournalEnvironmental health perspectives
Volume125
Issue number6
DOIs
StatePublished - Jun 2017

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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