Polymorphisms in oxidative stress, metabolic detoxification, and immune function genes, maternal exposure to ambient air pollution, and risk of preterm birth in Taiyuan, China

Highlights

• An increase in air quality index (AQI) was slightly associated with an increased risk of PB.

• Genetic variants in genes involved in oxidative stress and immune function modified the association between AQI and PB risk.

• Statistically significant associations between AQI and PB were observed among women who carried GPX4-rs376102, GLRX-rs889224, VEGFA-rs3025039, and IL1A-rs3783550 polymorphisms.

• GPX4-rs376102 and AQI interaction remained statistically significant after adjustment for multiple comparisons.

Abstract

Exposure to air pollutants may be associated with preterm birth (PB) through oxidative stress, metabolic detoxification, and immune system processes. However, no study has investigated the interactive effects of maternal air pollution and genetic polymorphisms in these pathways on risk of PB. The study included 126 PB and 310 term births. A total of 177 single nucleotide polymorphisms (SNPs) in oxidative stress, immune function, and metabolic detoxification-related genes were examined and analyzed. The China air quality index (AQI) was used as an overall estimation of ambient air pollutants. Among 177 SNPs, four SNPs (GPX4-rs376102, GLRX-rs889224, VEGFA-rs3025039, and IL1A-rs3783550) were found to have significant interactions with AQI on the risk of PB (P_interaction were 0.001, 0.003, 0.03, and 0.04, respectively). After being stratified by the maternal genotypes in these four SNPs, 1.38 to 1.76 times of the risk of PB were observed as per interquartile range increase in maternal AQI among women who carried the GPX4-rs376102 AC/CC genotypes, the GLRX-rs889224 TT genotype, the VEGFA-rs3025039 CC genotype, or the IL1A-rs3783550 GT/TT genotypes. After adjustment for multiple comparisons, only GPX4-rs376102 and AQI interaction remained statistically significant (false discovery rate (FDR)=0.17). After additional stratification by preeclampsia (PE) status, a strongest association was observed in women who carried the GPX4-rs376102 AC/CC genotypes (OR, 2.26; 95% CI, 1.41–3.65, P_interaction=0.0002, FDR=0.035) in the PE group. Our study provided the first evidence that association between maternal air pollution and PB risk may be modified by the genetic polymorphisms in oxidative stress and immune function genes. Future large studies are necessary to replicate and confirm the observed associations.

Introduction

Preterm birth (PB) is a significant clinical and public health problem due to its high prevalence and associated neonatal mortality, childhood morbidity, as well as chronic diseases in adulthood (Falah et al., 2013). However, the etiology of PB remains unclear, with few established risk factors. Several lines of evidence have suggested that genetic predisposition plays an important role in PB (Monangi et al., 2015; Chawla, 2018). Many scientific works have demonstrated that genetic polymorphisms in oxidative stress genes may be independent predictors for PB and/or prematurity complications (Chawla, 2018; Giusti et al., 2012; Costantine et al., 2012; Tsai et al., 2008; Sram et al., 1999; Vora et al., 2017). Several antioxidant enzymes including glutathione peroxidase (GPX) and glutathione reductase (GR) have been found to be significantly higher in the placenta of women having PB than those having full term birth (Ahamed et al., 2009; Jacob-Ferreira et al., 2010). Recent studies found that genetic polymorphisms in metabolic detoxification-related genes (i.e. cytochrome P450 1A1 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), and theta 1 (GSTT1)) modulated risk of PB associated with exposure to environmental toxicants (Behrman and Butler, 2007) including heavy metals (Wang et al., 2000; Shachar et al., 2013), pesticides (Mustafa et al., 2013), and cigarette smoking (Tsai et al., 2008; Nukui et al., 2004). Candidate gene studies have shown that some genetic variants in immune system (MBL2, NOS2, IL1, TNF, etc.), are significantly associated with PB (Strauss et al., 2018; Silva et al., 2020).

Particulate matter (PM), along with ozone (O₃), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and carbon monoxide (CO) are the common harmful ambient air pollutants (Criteria Air Pollutants.). PM₁₀ (particles <10 μm in aerodynamic diameter) and PM_2.5 (<2.5 μm) include inhalable particles that are small enough to penetrate the thoracic region of the respiratory system. There are serious risks to health not only from exposure to PM, but also from exposure to O₃, NO₂, SO₂ and CO. As with PM, concentrations are often highest largely in the urban areas of low- and middle-income countries (Koren, 1995). NO₂ and SO₂ play an important role in PB (Ambient Outdoor Air Pollution, 2014; Sheikh et al., 2016). It has been suggested that CO is a significant mediator of cardiovascular status following PB (Stark et al., 2009). The World Health Organization (WHO) estimates that the majority of outdoor air pollution-related premature deaths were due to ischemic heart disease, strokes, chronic obstructive pulmonary disease or acute lower respiratory infections, and lung cancer. Thus, exposure to various ambient air pollutants is of particular relevance to pregnancy outcomes, including PB. However, the effects of the mixture of those five ambient air pollutants on PB have not yet been studied, particularly in high air pollution areas. In 2013, Beijing launched a four-color alert system based on the air quality index (AQI), which is calculated based on the levels of the five aforementioned ambient air pollutants, and has been applied to all cities in China to indicate how clean or polluted the air is. We have reported positive associations between exposure to higher levels of PM₁₀ and PM_2.5 exposure during pregnancy and risk of PB and abnormal fetal growth in our previous studies performed in Northern China (Zhao et al., 2015, 2018; Cheng et al., 2016), but the overall combined effect of maternal exposure to air pollution estimated from PM, O₃, NO₂, SO₂, and CO on risk of PB is not well known.

Emerging evidence suggested that genetic variations could modify the relationship between air pollution and the risk of PB (Sheikh et al., 2016). Only one study has investigated genetic variation in metabolic detoxification genes modulating the risk of PB associated with maternal exposure to ambient air pollution (Suh et al., 2008). No study, however, has examined the joint effects of genetic variation in oxidative stress and immune function pathways and ambient air pollution on the risk of PB.

Taken together, exposure to air pollutants may be associated with PB through oxidative stress, metabolic detoxification, and immune function processes, and such an association may be further modified by polymorphisms in genes involved in these pathways. In order to address the important gap in literature regarding this research question, we used a candidate gene approach to investigate whether the relationship between maternal exposure to ambient air pollution and risk of PB is modulated by single nucleotide polymorphisms (SNPs) involved in oxidative stress, metabolic detoxification, and immune function processes in a Chinese population.