Elsevier

Gene

Volume 626, 30 August 2017, Pages 414-419
Gene

Genetic variants in autophagy associated genes are associated with DNA damage levels in Chinese population

https://doi.org/10.1016/j.gene.2017.05.017Get rights and content

Highlights

  • Seven functional polymorphisms in ATGs were analyzed in 307 Chinese subjects.

  • Rs12599322 and rs7484002 were significantly associated with DNA damage levels.

  • A significant dosage effect exits between risk allele numbers and DNA damage levels.

  • These two SNPs may modify DNA damage by regulating surrounding genes expression.

Abstract

Autophagy associated genes (ATGs) played an important role in the repair process of DNA damage and decreased autophagy may weaken the repair process and aggravate DNA damage. Based on this, we hypothesized that DNA damage levels might be modified by genetic variants in autophagy associated genes. In order to validate our hypothesis, 307 subjects were recruited from three different cities (Zhuhai, Wuhan and Tianjin) in China. Demographic data, individual 24-h PM2.5 exposure and peripheral blood DNA damage levels were also detected. Seven potentially functional polymorphisms in four essential autophagy associated genes (ATG5, ATG7, ATG8 and ATG13) were screened to evaluate the relationship between the polymorphisms of autophagy associated genes and DNA damage levels. This association was assessed by using multivariable linear regression model, age, sex, smoke and PM2.5 exposure levels were adjusted in each city. We found that rs12599322 in ATG8 (A > G, β = 0.263, 95% CI: 0.108–0.419, P = 8.98 × 10 4) and rs7484002 in ATG13 (A > G, β = 0.396, 95% CI: 0.085–0.708, P = 0.013) were significantly associated with higher DNA damage levels. Furthermore, functional annotations showed that both rs12599322 and rs7484002 located at transcription factor binding sites (TFBS), indicating that they could regulate the expression of related genes through TF regulation. Following allelic trend analysis revealed that the DNA damage levels were significantly aggravated with the increasing number of risk variants in autophagy associated genes (P for trend: 8.09 × 10 5). Our findings suggested that the polymorphisms in ATGs may influence DNA damage levels in one of the Chinese population.

Introduction

In recent years, air pollution has become a serious threat to human health (Ouyang, 2013). Epidemiology studies suggested that air pollution contributed to the increased morbidity and mortality of respiratory diseases, including lung cancer, chronic obstructive pulmonary disease (COPD), asthma and so on (Zhou et al., 2015, Guo et al., 2016, Fisher et al., 2016).

DNA damage is a common event which can be generated from environmental agents (such as ultraviolet light, ionizing radiation) and internal factors (such as reactive oxygen) (Jackson and Bartek, 2009). Many studies have demonstrated that unrepaired DNA damage played a key role in the process of cancer development (Jackson and Bartek, 2009, Hoeijmakers, 2009). Currently, one of the most important air pollutions in China is the accumulation of PM2.5. PM2.5 is also named fine particulate matter whose aerodynamic diameter ≤ 2.5 μm. Studies have shown that PM2.5 contributed to the risk of respiratory and cardiovascular diseases (Brook and Rajagopalan, 2010, McGuinn et al., 2016). PM2.5 is easy to absorb some organic chemicals, heavy metals and so forth. Many researches have proved that PM2.5 could aggravate DNA damage, oxygen free radicals induced by heavy metals and other substances or the formation of PAH-DNA adducts may be the potential mechanisms (Topinka et al., 2011, Deng et al., 2013, Hu et al., 2008, Perera et al., 2011). However, people who exposed to the similar environment may have different DNA damage levels, which indicated that genetic variants could also modify the DNA damage (Chu et al., 2015, Huang et al., 2012).

Autophagy is a crucial cellular process. Oxidative stress, starvation and diversified other stimuli could regulate this response (Rodriguez-Rocha et al., 2011). During this process, cell solute and organelles were wrapped up within double-membrane vesicles which would be carried to the lysosome or vacuole (Klionsky, 2005). Previous studies have demonstrated that autophagy could modify DNA damage repair, and the disorder of autophagy might result in the accumulation of DNA damage through the increase of oxidative stress and other mechanisms (Jin and White, 2007, Panda et al., 2015).

Based on these studies, we assumed that polymorphisms in ATGs could regulate DNA damage levels. In order to validate our hypothesis, 307 subjects were recruited from three different cities (Zhuhai, Wuhan and Tianjin) in China, relevant information, such as demographic data, 24-h PM2.5 exposure levels were collected. Seven potentially functional polymorphisms in four selected essential autophagy associated genes (ATG5, ATG7, ATG8, ATG13) were screened to evaluate the relationship between the polymorphism of autophagy associated genes and DNA damage by using multivariable linear regression model.

Section snippets

Study subjects

In the beginning, 328 subjects were enrolled in this research. All of these subjects were from three different cities (Zhuhai: 119; Wuhan: 123; Tianjin: 86), detailed information about the subjects please refer to our previous papers (Gong et al., 2014, Liu et al., 2016). Briefly, all participants were interviewed to gather demographic data and epidemiological information. Gilian 5000 pumps were used to measure individual 24-h PM2.5 exposure levels. 21 participants were further excluded because

Baseline information of 307 subjects

The basic information and epidemiological information are summarized in Supplementary Table 1. PM2.5 exposure levels in three cities were different (median value: 68.35 μg/m3 (Zhuhai), 114.96 μg/m3 (Wuhan) and 146.60 μg/m3 (Tianjin)). The median percentages of tail DNA are 1.36% (Zhuhai), 1.85% (Wuhan) and 2.97% (Tianjin) respectively in three cities. And we then divided all the participants into four groups according to the quartile of PM2.5 exposure levels to study the relationship between

Discussion

This study aimed to explore the relationship between genetic variants in ATGs and DNA damage. Seven potentially functional polymorphisms in these four ATGs were included in this study, and two SNPs (rs12599322 and rs7484002) were identified to be associated with DNA damage levels.

In our previous studies, we explored the association between genetic variants in SMARC and multisynthetase complex genes and DNA damage levels (Gong et al., 2014, Liu et al., 2016). We successfully identified several

Author disclosure statement

The authors declare that they do not have competing financial interest.

Acknowledgments

This work was funded by the National Key Basic Research Program Grant (2011CB503805), the National Natural Science Foundation of China (81521004, 81230067, 81390543), the Priority Academic Program for the Development of Jiangsu Higher Education Institutions [Public Health and Preventive Medicine] and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067). The authors are grateful to all the study participants.

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    These authors contributed equally to this work.

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