AS264 - Modification of PM-mediated arrhythmogenesis in populations (MOPMAP)

Investigator Names and Contact Information

Eric A. Whitsel, MD MPH

Introduction/Intent

We propose a study of the susceptibility to the arrhythmogenic effects of particulate matter (PM) air pollution contributed by common genetic and environmental variation. Its rational derives from the established, but heterogeneous association between ambient levels of PM pollution and acute coronary heart disease (CHD) events, a widespread, but poorly understood threat to public health. The proposed study focuses on carefully selected, resting, standard twelve-lead ECG measures that have been linked to ambient PM concentrations and to acute CHD events. It will optimally leverage genomic, environmental and electrocardiographic data from the Women's Health Initiative (WHI) and its ancillary study, "The Environmental Epidemiology of Arrhythmogenesis in WHI" (AS #140, Whitsel, PI). Specifically, we will examine measures of heart rate variability, ventricular repolarization, myocardial ischemia and ventricular ectopy within five distinct subpopulations of WHI clinical trial (CT) participants living ≤ 500 miles away from their exam sites at the time of their first-recorded, high-quality ECGs between 1999 and 2004. Subpopulation I (1500 Northeast Whites from U.S. Environmental Protection Agency [EPA] Regions 1-2) will be randomly sampled. It will be used to identify potential gene-by-environment interactions between approximately 55,000 cardiovascular disease-related single nucleotide polymorphisms (SNPs) genotyped on the Illumina CARe microarray and daily mean ambient PM concentrations spatially interpolated at geocoded participant addresses. Subpopulations II and III (2250 Southwest Whites from EPA Region 9 and 2250 Blacks from EPA Regions 1-10) also will be randomly sampled. They will be used to replicate examination of the most promising 1% of SNPs identified in Population I. Subpopulation IV (1507 Whites with ventricular ectopy) will be sampled from EPA Regions 1-10, and subpopulation V (1507 Whites without ventricular ectopy) from the same exam sites and periods within which the ectopy cases arose. Collectively, the cases and controls will form the basis of an analysis targeting gene-by-environment interactions as they relate to this dichotomous ECG outcome. All analyses will be well-powered and appropriately adjusted for both ancestral admixture and multiple comparisons. Anticipated findings will substantially increase understanding of susceptibility to and the pathophysiological mechanisms underlying PM-mediated arrhythmogenesis.

Specific Aims

The research described in this proposal examines the contributions of genetic susceptibility and environmental factors to the arrhythmogenic effects of particulate matter (PM) air pollution. The proposal draws on the extant characterization of Women's Health Initiative clinical trial (WHI CT) participants, on their exposure to ambient PM, and on electrocardiographic measures that have been linked to ambient PM concentrations on the one hand, and acute coronary heart disease (CHD) events on the other. The study's specific aims are to:

1. Sample five distinct subpopulations of WHI CT participants living ≤ 500 miles away from their exam sites at the time of their first-recorded, high-quality resting, standard twelve-lead electrocardiograms (ECGs) between 1999 and 2004

   • a. I: 1500 Northeast Whites (EPA Regions 1-2)

   • b. II: 2250 Southwest Whites (EPA Region 9)

   • c. III: 2250 Blacks (EPA Regions 1-10)

   • d. IV: 1507 Whites with ventricular ectopy (EPA Regions 1-10)

   • e. V: 1507 Whites without ventricular ectopy (same exam sites & periods in which IV arose)

2. Perform Phase 1 genotyping and genetic epidemiologic analyses

   • a. genotype approximately 55,000 cardiovascular disease (CVD)-related single nucleotide polymorphisms (SNPs) in Subpopulations I, IV & V using the CVDSNP55 microarray

   • b. genotype approximately 384 SNPs identified from published genome-wide association and candidate gene studies in Subpopulations I, IV & V using the 384 Goldengate microarray

   • c. conduct genetic epidemiologic analyses designed to prioritize CVD-related SNP-PM interactions as they relate to heart rate variability, ventricular repolarization and myocardial ischemia in Subpopulation I

   • d. conduct genetic epidemiologic analyses designed to prioritize CVD-related SNP-PM interactions as they relate toventricular ectopy in Subpopulations IV & V

3. Perform Phase 2 genotyping and replication analyses

   • a. genotype the most promising 1% of SNPs (550) and approximately 218 ancestry informative markers (AIMs) from Phase 1 in Subpopulations II & III using the 768 Goldengate microarray

   • b. conduct genetic epidemiologic analyses designed to prioritize CVD-related SNP-PM interactions as they relate to heart rate variability, ventricular repolarization and myocardial ischemia in Subpopulations II & III

4. Examine the robustness of findings across alternative

   • a. methodological approaches

   • b. electrocardiographic metrics

   • c. pollutant metrics

5. And thereby

   • a. Endow WHI with high quality CVD-related SNP data on a total of 9014 WHI CT participants

   • b. Improve understanding of genetic susceptibility to and the pathophysiological mechanisms underlying PMmediated arrhythmogenesis

   • c. Inform epidemiologists, environmental health scientists, and federal regulators responsible for accurately evaluating air quality standards in terms of their ability to protect the cardiovascular health of women living in the U.S.