Genome-wide Association Study of Susceptibility to Particulate Matter-Associated QT Prolongation

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 <em>CXCL12</em>, 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. https://doi.org/10.1289/EHP347

Figure 1.

Manhattan plot of $-{\log }_{10}$ p-value vs. chromosomal position of each SNP from the trans-ethnic, fixed-effects meta-analysis of the $\text{SNP}\times {\text{PM}}_{10}$ interactions. The red line references the genome-wide significance threshold (p-value$<5.0\times {10}^{-8}$).

Figure 2.

Regional plots of the locus, rs1619661, identified by the trans-ethnic, fixed-effects meta-analysis of the $\text{SNP}\times {\text{PM}}_{10}$ interactions, on chromosome 10, near CXCL12. Each point represents the $-{\log }_{10}$p-value of a SNP plotted as a function of its genomic position (build 37) and the genome-wide significance threshold (p-value$<5.0\times {10}^{-8}$). One SNP reached this threshold. The color coding of all other SNPs indicated linkage disequilibrium with this lead SNP, estimated among Africans (A), Ad-mixed Americans (B), and Europeans (C) from 1000G. Recombination rates were estimated from the 1,000 Genomes Project.

Figure 3.

Forest plot of $\text{SNP}\times {\text{PM}}_{10}$ interaction (95% confidence interval) per T allele increase in rs1619661 (genotype CT) at ${\text{PM}}_{10}$ concentrations $>90\text{th}$ percentile, by study, race/ethnicity, and overall (${\mathrm{P}}_{\text{Cochran}\prime \mathrm{s}\text{Q}}=0.14$).

Figure 4.

Predicted mean (95% confidence interval) QT (ms) per unit increase in the coded allele (T) dosage of rs1619661 at ${\text{PM}}_{10}$ concentrations $\le$ and $>90\text{th}$ percentile (P90), while adjusting for age, geographic region or center, season, calendar year, RR interval, and ancestry. C allele frequency range: 8–19%.