Abstract P364: Genetic Susceptibility to Particulate Matter-Associated QT Prolongation in a Trans-Ethnic Genome-Wide Association Study
Background: QT prolongation_an electrocardiographic risk factor for ventricular arrhythmia and sudden cardiac death_has both a genetic and environmental etiology. However, genetic susceptibility to particulate matter-associated QT interval (QT) prolongation has not been characterized.
Methods: To characterize such susceptibility in a genome-wide association study, we conducted cohort-, race/ethnicity-, and sex-stratified longitudinal analyses of eight Women’s Health Initiative clinical trials (WHI CT) and Atherosclerosis Risk in Communities study (ARIC) subpopulations (total n: 20,595; mean age: 63.4 yrs; 77% female; 28% black; mean visits/person: 3.0). In each subpopulation, we used generalized estimating equation (GEE) methods adapted for small sample size to estimate interactive effects of dichotomized daily mean concentrations of ambient particulate matter < 10 μm in diameter (PM10 ≤ or > subpopulation-specific 90th percentiles) and approximately 2.5 million imputed single nucleotide polymorphisms (SNPs), while adjusting for age, geographic region or center, season, calendar year, RR(ms) and ancestral admixture. Subpopulation-specific SNP-PM10 interaction effects were meta-analyzed using fixed-effects, inverse variance-weighted, meta-analysis with genomic control.
Results: A common variant (rs1619661; minor allele frequency range: 9% - 20%) was associated with QT prolongation in seven (88%) of the eight subpopulations (overall P = 8.2 x 10-8). The variant is on chromosome 10, 150 kb downstream from CXCL12, which encodes a chemokine stromal-cell derived factor 1 (SDF-1) that is expressed in cardiac myocytes, affects calcium homeostasis, and has an established role in both diabetogenesis and atherosclerosis. QT increased 2.6 and 0.0 ms per unit increase in dosage of the variant at PM10 concentrations > and ≤ the 90th percentile, respectively.
Conclusions: The preliminary findings from this longitudinal genome-wide association study suggest that biologically plausible genetic factors may affect susceptibility to PM10-associated QT prolongation in racially, geographically and environmentally diverse populations protected by U.S. EPA National Ambient Air Quality Standards.has both a genetic and environmental etiology. However, genetic susceptibility to particulate matter-associated QT interval (QT) prolongation has not been characterized.
Author Disclosures: R. Gondalia: None. O. Mopmap: None.
- © 2015 by American Heart Association, Inc.