Glutathione-S-transferase M1, obesity, statins, and autonomic effects of particles: gene-by-drug-by-environment interaction

Abstract

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 microM in aerodiameter (PM2.5) and HF in 497 participants in the Normative Aging Study, using linear regression controlling for covariates.

Main results: A 10-microg/m3 increase in PM2.5 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 PM2.5. Obesity and high neutrophil counts also worsened the PM effects with or without GSTM1.

Conclusion: The effects of PM2.5 on HF appear to be mediated by reactive oxygen species. This may be a key pathway for the adverse effects of combustion particles.

Figure 1.

The estimated covariate-adjusted percentage decrease in the high-frequency (HF) component of heart rate variability (and 95% confidence interval) that is associated with a 10-μg/m³ increase in concentrations of particles less than 2.5 μM in aerodiameter (PM_2.5) is shown for persons with (G0) and without (G1) the deletion of the GSTM1 gene (left side), and for persons with (S1) and without (S0) statin use (right side). The covariates controlled were age, cigarette smoking, body mass index, diastolic blood pressure, fasting blood glucose, alcohol consumption, use of β-blockers, use of angiotensin-converting enzyme inhibitors, use of calcium channel blockers, season, room temperature, and outdoor temperature. The numbers below the labels are the number of subjects in each analysis.

Figure 2.

The estimated covariate-adjusted percentage decrease in the HF component of heart rate variability (and 95% confidence interval) associated with a 10-μg/m³ increase in PM_2.5 concentrations is shown for persons who are (S1) and are not (S0) taking a statin, with (G0) or without (G1) the deletion of GSTM1. The covariates controlled are as in Figure 1. The number of subjects in each category is listed below the category label.