eNOS gene polymorphisms modify the association of PM₁₀ with oxidative stress

Abstract

Previous studies have suggested that air pollution increases various health outcomes through oxidative stress and oxidative stress-related genes modify the relationship between air pollution and health outcomes. Therefore, we evaluated the effect of PM₁₀ on the levels of malondialdehyde (MDA), oxidative stress biomarker, and the effect modification by genetic polymorphisms of eNOS, oxidative stress-related gene, in the 560 Korean elderly. We obtained urine samples repeatedly from participants during five medical examinations between 2008 and 2010 and all ambient air pollutant concentration data from the Korea National Institute of Environmental Research air quality monitoring system. We measured urinary levels of MDA to assess oxidative stress and genotyped eNOS (rs1799983, rs2853796, and rs7830). Mixed-effect model was used to estimate the effect of PM₁₀ on the level of oxidative stress biomarker and their modification by genotypes. PM₁₀ showed apparent positive effect on MDA level after adjusting for age, sex, BMI, cotinine level, temperature, dew point, levels of SO₂, O₃, NO₂, and CO, and season (p = 0.0133). Moreover, the association of PM₁₀ with MDA was found only in participants with eNOS GG genotype for rs1799983 (p = 0.0107), TT genotype for rs2853796 (p = 0.0289), or GT genotype for rs7830 (p = 0.0158) and in participants with a set of risky haplotypes (GTT, GTG, GGT, and TGT) (p = 0.0093). Our results suggest that PM₁₀ affect oxidative stress in the elderly and eNOS genotype affect the oxidative stress level in regard of exposure to PM₁₀.

Introduction

Air pollution has been reported to contribute to respiratory and cardiovascular morbidity and mortality, including asthma, myocardial infarction, and stroke (de Kok et al., 2006, Hong et al., 2002, Maynard et al., 2007, Schwartz and Morris, 1995). Recent research has suggested oxidative stress is a major biologic pathophysiological mechanism underlying the effect of air pollutants, specifically in particulate air pollutant (Kodavanti et al., 2001, Møller et al., 2008, Romieu et al., 2010, Rossner et al., 2008, Schwartz et al., 2005). However, our understanding is still limited on whether particulate matter less than 10 μm (PM₁₀) causes oxidative stress in human subjects.

Oxidative stress is induced by an impaired balance between free radical production and antioxidant capacity resulting in excess oxidative products (Hong et al., 2009). The generation of reactive oxygen species can cause oxidative damage to constituter such as DNA, proteins, or lipids in the body. Malondialdehyde (MDA), which is an end product of the oxidation of polyunsaturated fatty acids and can determine the degree of lipid peroxidation, has been used as a marker for oxidative stress (Benzie, 1996, Gutteridge and Halliwell, 1990). Therefore, in this study, we tried to determine whether exposure to PM₁₀ increases urinary concentrations of MDA in the elderly.

In previous studies, it has been difficult to capture within-subject changes because of their cross-sectional nature of the associations. To account for within-subject changes in oxidative stress, a longitudinal study with repeated measurements is required. Because each subject can be used as his or her own control with repeated measurements, the panel study design has the advantage that only rapidly changing covariates for each given subject must be considered in a statistical analysis. Therefore, in this study, we conducted longitudinal panel study with repeated measurements to estimate acute effect of PM₁₀ on oxidative stress.

If oxidative stress is a major biologic pathophysiological mechanism underlying the effect of air pollutants (Romieu et al., 2008), genes involved in oxidative stress can be logical candidates for studying air pollution–gene interactions (Romieu et al., 2010). Endothelial nitric oxide synthase (eNOS) gene has attracted interest because of the function for production of nitric oxide in endothelial cells, regulation of vascular tone, inhibition of platelet and leukocyte adhesion to vascular endothelium, and inhibition of vascular smooth muscle cell migration and growth, and antioxidation and antiapoptosis (Hingorani et al., 1999, Karvonen et al., 2002, Loscalzo and Welch, 1995, Lowenstein et al., 1994, Vanhoute, 1997). Variations in this gene have been reported to be associated with susceptibility to a variety of diseases (Karvonen et al., 2002, Sharma et al., 2011). Therefore, in this study, we also evaluated the effect modification of exposure to PM₁₀ on oxidative stress by eNOS gene polymorphisms in the elderly.