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Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles

Gene-by-Drug-by-Environment Interaction

Department of Environmental Health, Harvard School of Public Health; Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School; VA Boston Healthcare System; and the Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Joel Schwartz, Ph.D., Exposure, Epidemiology and Risk Program, Harvard School of Public Health, Landmark Center West, Suite 415, 401 Park Drive, P.O. Box 15698, Boston, MA 02215. E-mail: jschwrtz{at}hsph.harvard.edu

Rationale: Air pollution by particulate matter (PM) has been associated with cardiovascular deaths, although the mechanism of action is unclear. One proposed pathway is through disturbances of the autonomic control of the heart.

Objectives: We tested the hypothesis that such disturbances are mediated by PM increasing oxidative stress by examining the association between PM and the high-frequency (HF) component of heart rate variability as modified by the presence or absence of the allele for glutathione-S-transferase M1 (GSTM1) and the use of statins, obesity, high neutrophil counts, higher blood pressure, and older age.

Methods: We examined the association between particles less than 2.5 µM in aerodiameter (PM_2.5) and HF in 497 participants in the Normative Aging Study, using linear regression controlling for covariates.

Main Results: A 10-µg/m³ increase in PM_2.5 during the 48 h before HF measurement was associated with a 34% decrease in HF, 95% confidence interval (–9%, –52%), in subjects without the allele, but had no effect in subjects with GSTM1 present. Among GSTM1-null subjects, the use of statins eliminated the effect of PM_2.5. Obesity and high neutrophil counts also worsened the PM effects with or without GSTM1.

Conclusion: The effects of PM_2.5 on HF appear to be mediated by reactive oxygen species. This may be a key pathway for the adverse effects of combustion particles.

Key Words: genetic polymorphisms • heart rate variability • oxidative stress • particles

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