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

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.