Research paperGenetic variations in inflammation-related genes and their influence on the susceptibility of pediatric acute lung injury in a Chinese population
Introduction
Acute lung injury (ALI) is a serious, rapid-onset clinical syndrome which disrupts normal oxygen exchange in the lungs and can lead to respiratory failure among critically ill patients, in the absence of cardiac failure. The syndrome is characterized by increased vascular permeability, which results in pulmonary oedema and interstitial pulmonary fibrosis, and more importantly, excessive and profound inflammation (Goodman et al., 2003). To be categorized as ALI, the patient should have a ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of between 201 and 300 mm Hg. Clinical risk factors for ALI include, but not limited to, sepsis, pneumonia, trauma, pancreatitis, septic shock, multiple transfusions and gastric aspiration (Wang et al., 2014; Kim and Hong, 2016). However, only about 50% of individuals with the risk factors above experience ALI, while the remaining individuals with similar type and severity of the medical conditions are not affected (Matsuda et al., 2012).
Genetic variants have been proposed to influence the susceptibility to ALI (Flores et al., 2010). Given the fact that exaggerated inflammation represents a hallmark of ALI, a number of studies have investigated the association between variants in inflammation-related genes and ALI (Flores et al., 2010; Reddy and Kleeberger, 2009; Dias et al., 2009). Several significant associations have been observed (O'Mahony et al., 2012; Flores et al., 2008; Meyer et al., 2012). However, the influence of genetic variations is known to differ from population to population, and there is a limited number of genetic association studies on ALI in China. Moreover, it has been suggested that the pathogenesis of ALI in adults could be different from pediatric ALI (PALI) (Pediatric Acute Lung Injury Consensus Conference Group, 2015). Currently, the association between genetic polymorphisms and PALI remains unclear.
In this work, we investigated the association between 12 polymorphisms in six inflammatory-response genes and risk of PALI. The genes and polymorphisms examined were IL6 (rs1800795, rs1800796, rs1800797), IL10 (rs1800896, rs3021097), NFKB1 (rs28362491), NFKBIA (rs2233406, rs696), IL18 (rs1946518, rs187238) and TNF (rs1799964, rs1800629). These genes were chosen because their protein product has been shown to play important roles in lung injuries (Bhargava et al., 2013; Yang et al., 2017; Li et al., 2015; Sekine et al., 2009; Filgueiras Jr et al., 2012; Li et al., 2016; Patel et al., 2013; Song et al., 2001). IL6 encodes for interleukin-6, whose increased expression has been observed in AKI patients (Bhargava et al., 2013). Interleukin-6 is known to be able to recruit inflammatory cells into the alveolar air spaces and activates the ERK signaling cascade and several other signal transduction pathways, thus mediating the process of inflammation (Cross and Matthay, 2011). On the other hand, IL18 encodes interleukin-18, which has been shown to be present at a higher level with an increasing severity of lung injury (Kikkawa et al., 2009). Interleukin-18 is known to induce interferon gamma activation, which can recruit neutrophils to the lungs (Cross and Matthay, 2011). Unregulated release of various compounds by the neutrophils can damage the lung tissues, thus causing ALI (Grommes and Soehnlein, 2011). Besides, the products of IL10, NFKB1, NFKBIA and TNF work in close relationship with one another during the pathogenesis of ALI. IL10 encodes interleukin-10, which can inhibit Th1 differentiation and inhibit neutrophil recruitment and activation, thus causing an altered level of cytokines, nitric oxide and matrix metalloproteinases needed for proper regulation of the lung function (Li et al., 2015; Cross and Matthay, 2011). An increased plasma level of interleukin-10 has been reported in ALI (Cross and Matthay, 2011). Interleukin-10 may exert its function by inhibiting the degradation of the nuclear factor kappa inhibitor (IκBα, encoded by NFKBIA), thus allowing a constitutive activation of nuclear factor kappa beta (NF-κβ, encoded by NFKB1), which can regulate the expression of many proinflammatory cytokines (Filgueiras Jr et al., 2012; Li et al., 2016; Wu et al., 2009). Among the most potent proinflammatory cytokines regulated by NF-κβ is tumor necrosis alpha, which is encoded by TNF. Levels of tumor necrosis alpha have been observed to be higher in ALI (Li et al., 2012). The cytokine can provoke an inflammatory cascade in the lung, which causes tissue injury and alveolar epithelial dysfunction, thus leading to ALI (Patel et al., 2013; Song et al., 2001).
All polymorphisms studied are located in the promoter region of the respective genes and may influence the transcription (and in some cases, secretion) of the protein product, with the exception of NFKBIA rs696, which is located at the regulatory 3′ UTR region of the gene. We hypothesized that the above polymorphisms could be associated with risk of PALI among our population, and this study was conducted to investigate this hypothesis.
Section snippets
Study subjects
This is a retrospective study utilizing samples stored previously in the Pediatric Biobank of The First People's Hospital of Bijie. To be included into the study, cases must meet the definition of ALI based on the American-European Consensus Committee (AECC) criteria, whereas controls comprised children who had clinical risk factors for PALI (such as sepsis, trauma, or pneumonia) and acute kidney injury (AKI) but did not eventually develop the syndromes (Note: risk factors for AKI was taken
Subject characteristics
The characteristics of the study population are shown in Table 3. A total of 1075 cases and 1382 controls were included. The mean age of cases was 8.01 ± 4.30 years old (range: 1–15 years, median: 8 years), while the mean age of controls was 8.46 ± 4.69 years old (range: 1–16 years, median: 8). The age difference between cases and controls was statistically significant (P = 0.015). Among the cases, 584 (54.3%) were males and 491 (45.7%) were females, while 756 (54.7%) among the controls were
Discussion
Inflammation represents one of the most prominent features of ALI (Goodman et al., 2003; Patel et al., 2012). Only a few studies have been conducted previously to investigate this association between inflammatory gene polymorphisms with risk of ALI. None of these studies was conducted on the pediatric population. Moreover, it has been suggested that the pathobiology of ALI in adults could be different from that in children (Pediatric Acute Lung Injury Consensus Conference Group, 2015). In this
Acknowledgement
This study was supported by Science and Technology fund from Bijie City ([2013]63).
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These two authors contribute to this work equally.