Academic journal article Environmental Health Perspectives

Particulate Air Pollution, Oxidative Stress Genes, and Heart Rate Variability in an Elderly Cohort

Academic journal article Environmental Health Perspectives

Particulate Air Pollution, Oxidative Stress Genes, and Heart Rate Variability in an Elderly Cohort

Article excerpt

Particulate air pollution (PM) is associated with increased risk of hospitalization and death from cardiovascular disease (Brook et al. 2004; Forastiere et al. 2005; Samet et al. 2000; Schwartz 1999; Zanobetti and Schwartz 2005), but the mechanisms underlying such effects are not fully understood. Reductions in heart rate variability (HRV), a noninvasive measure that independently predicts cardiovascular mortality (Tsuji et al. 1996), have been related to PM exposure, particularly to fine-particulate air pollution of < 2.5 [micro]m in aerodynamic diameter ([PM.sub.2.5]) (Creason et al. 2001; Devlin et al. 2003; Gold et al. 2000; Holguin et al. 2003; Liao et al. 2005a; Magari et al. 2002; Park et al. 2005; Pope et al. 2004; Schwartz et al. 2005a).

Animal experiments indicate that reactive oxygen species (ROS), which have established relevance in the pathogenesis of cardiovascular disease (Dhalla et al. 2000), are potential mediators for particle effects on HRV and other cardiovascular end points (Brook et al. 2004; Gurgueira et al. 2002; Nel 2005; Rhoden et al. 2004). While animal models can identify potential mechanisms of particle effects, the relative importance of these pathways in humans at lower doses is not clear and may be determined by examining subjects with genetically determined differences in oxidative-stress defenses. In elderly subjects living in the Boston, Massachusetts, metropolitan area, we recently showed that [PM.sub.2.5] levels during the 48 hr before the study were associated with decreased HRV in individuals with the glutathione S-transferase M1 (GSTM1) deletion, but had no effect in subjects with GSTM1 present (Schwartz et al. 2005b).

Studies showing the effect of just one polymorphism are unlikely to correctly represent the complex etiology of common diseases, and failure to account for gene-gene interactions in the search for susceptibility genes has been widely suggested to explain the persisting difficulties in replicating significant findings (Millstein et al. 2006). Particle exposure induces both heme oxygenase-1 (HMOX-1) and GSTM1 expression through activation of the genetic antioxidant response element (ARE) (Li et al. 2004). A high number of microsatellite (GT)n dinucleotide repeats in 5'-flanking region may reduce HMOX-1 inducibility by ROS and has been associated with increased risk of coronary artery disease in high-risk groups with hyperlipidemia, diabetes, or current smoking (Chen et al. 2002; Kaneda et al. 2002). Consequently, individuals with a high number of (GT)n repeats may be more susceptible to the effects of airborne particles.

We hypothesized that the gene encoding HMOX-1, which is involved in various aspects of responses against oxidative stress, may a) directly modify the effect of ambient PM on HRV and b) interact with GSTM1 to determine which subjects are susceptible to airborne particle effects. To establish the role of the antioxidant response pathway in determining the cardiovascular effects of airborne particles, we examined in the present study the association of [PM.sub.2.5] with HRV in a repeated measure study of elderly subjects from the Boston metropolitan area, and evaluated how that association was affected by genetic variation in the HMOX-1 and GSTM1 loci.

Materials and Methods

Study population. Our study population consisted of 539 white males from the Normative Aging Study (NAS), a longitudinal study of aging established in 1963 by the U.S. Veterans Administration (Bell et al. 1972). Between January 2000 and June 2005, all participants still presenting for examination (n = 676) were evaluated for HRV. Of these, 137 subjects were excluded because of heart arrhythmias, measurement time < 3.5 min, or missing potential confounding variables or HMOX-1 data. Among the remaining 539 subjects, GSTM1 data were available for 476 subjects, who had one (n = 314) or two (n = 162) HRV measurements. In subjects with multiple HRV measurements, the time interval between measurements was approximately 3 years. …

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