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

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. To characterize genetic susceptibility to PM-associated QT prolongation in a multi-racial/ethnic, genome-wide association study (GWAS). Using repeated electrocardiograms (1986-2004), longitudinal data on in diameter (), and generalized estimating equations methods adapted for low-prevalence exposure, we estimated approximately interactions among nine Women's Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (), then combined subpopulation-specific results in a fixed-effects, inverse variance-weighted meta-analysis. A common variant (rs1619661; coded allele: T) significantly modified the association (). At concentrations 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 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 channel. The findings suggest that biologically plausible genetic factors may alter susceptibility to -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. https://doi.org/10.1289/EHP347.