Role of interleukin-4 genetic polymorphisms and environmental factors in the risk of asthma in children

INTRODUCTION

Asthma is a chronic allergic inflammatory disease of the airway. It is estimated that there are currently 300 million asthma patients worldwide, and the associated morbidity and mortality rates have been steadily increasing (Masoli et al., 2004). The global economic burden of asthma exceeds that of tuberculosis, human immunodeficiency virus infection, and acquired immune deficiency syndrome combined (Wills-Karp et al., 1998), and this disease has become a major public health problem globally (Jaakkola and Jaakkola, 2012).

As a complex disease, the pathogenesis of asthma remains unclear (Cook and Saglani, 2016). However, several studies have shown that it involves inflammatory immune cells (Cook and Saglani, 2016), the secretion of inflammatory mediators, and cytokine interactions (Osei-Kumah et al., 2006), leading to immunoglobulin (Ig) E-mediated hypersensitivity and eosinophil infiltration of the airway, causing chronic inflammation (Wongratanacheewin, 2014). Several complex and diverse risk factors contribute to the development of asthma, involving environment, immunity, lifestyle, and psychology (Hovland et al., 2015; Toskala and Kennedy, 2015; Demirdag and Ramadan, 2016). Many studies concerning this condition have been carried out, mainly focusing on epidemiological and genetic risk factors. It is widely believed that the occurrence of asthma is determined by the compounded effects of numerous genes and environmental aspects, including gene-gene and gene-environment interactions (Gonzalez-Garcia et al., 2015). In recent decades, single nucleotide polymorphisms have become one of the most commonly studied types of sequence variation in investigations of the relationship between genetics and disease susceptibility (Sengler et al., 2002; Tulah et al., 2013).

Interleukin-4 (IL-4) is primarily produced by Th2 cells (Smallwood et al., 2016). The biological function of IL-4 principally comprises increasing B cell major histocompatibility complex class II molecule expression, promoting resting B cell FcεR expression, elevating secretion of IgE and IgG1 in the activation of B cells, and stimulating IgG to IgE class switching in an autocrine manner to facilitate the differentiation of Th2 cells, while inhibiting Th1 cell proliferation and the Th1 response (Antczak et al., 2016; Pattnaik et al., 2016).

To date, many investigations have tested the association between IL-4 polymorphisms and asthma risk, but their results have not been consistent (Micheal et al., 2013; Tang et al., 2014; Huang et al., 2015; Bal et al., 2016). Therefore, we performed a case-control study to analyze the relationship between three IL-4-related loci [rs2243250 (589 C/T) and rs2070874 (107 T/C) in IL-4, and rs1801275 (576 Q/R) in the IL-4 receptor α-chain gene (IL-4R)] and risk of childhood asthma. Moreover, the effects of interactions between environmental factors and genotypes on risk were also assessed.

MATERIAL AND METHODS

RESULTS

The general characteristics of the patients and control subjects are shown in Table 2. No statistically significant differences in average age or sex were observed between the two groups. Of the 317 asthma patients, 237 (75.00%) had positive SPT results. Concerning disease severity, 70 patients (22.01%) presented with intermittent, 50 (15.72%) with mild sustained, 87 (27.36%) with moderate continued, and 110 (34.91%) with severe sustained asthma. Table 2

Comparison of the general characteristics of each study group.

DISCUSSION

Bronchial asthma is one of the most common chronic diseases, particularly among children. Approximately 30-50% of childhood asthma cases persist into adulthood, and an estimated 4.4 million children in the USA suffer from this condition (Eaton et al., 2008; Boulet et al., 2012), with 10.9% of high school students being affected (Akinbami and Schoendorf, 2002). Asthma may gradually evolve into chronic obstructive pulmonary disease or pulmonary heart disease.

A series of polymorphisms associated with a variety of asthma phenotypes have been identified in the IL-4 gene. For instance, it has been suggested previously that the 589 C/T variant in the IL-4 promoter region is connected to decreased FEV1 (Lee et al., 2004). Such relationships have been confirmed in populations in Japan and the USA (Nambu and Holgate, 2009; Zahran and Bailey, 2013), but not China and Arabia (Al-Mazam and Mohamed, 2001; Chen et al., 2013). The IL-4 and IL-13 genes are located on chromosome 5q31, a site potentially linked to atopic asthma. Other studies have reported that IL-4R plays an important role in the occurrence of asthma (Cui et al., 2003). The protein encoded by this gene is a key functional component of Th2 cells. IL-4R-deficient mice are unable to produce IgE and exhibit a defective Th2 response, implying that IL-4R is important in IgE regulation, and that corresponding sequence variations can affect signal transduction and increase asthma risk (Barner et al., 1998). IL-4R has been considered as an important candidate gene in atopic asthma susceptibility (Barner et al., 1998). It has been reported that three IL-4R alleles, Ile50, Pro478, and Arg551, are related to susceptibility to asthma. Andrews et al. (2001) analyzed the association between asthma risk and IL-4R 576 Q/R genotypes, alleles, and haplotypes, finding that these variants are in linkage disequilibrium and are associated with development of atopic asthma. Other studies have also identified Gln576Arg as a risk factor for this condition. For instance, Rosa-Rosa et al. (1999) examined 149 asthma patients and 57 healthy controls, and established a strong association between the IL-4R 576Arg allele and asthma severity, suggesting that IL-4R is implicated in allergic asthma and may be used as a marker to classify the clinical severity of this disease. In our study, the IL-4 589 C/T and 107 T/C polymorphisms demonstrated no relationship with asthma susceptibility, whereas IL-4R 576 Q/R did.

However, some previous findings are inconsistent with the results of the present study and those of the above studies. For example, Mak et al. (2007) performed an investigation of 292 asthma patients and 292 healthy controls in Hong Kong, concluding that the IL-4 589 C/T and IL-4R Gln576Arg variants do not significantly correlate with asthma risk in this population. Hosseini-Farahabadi et al. (2007) studied 30 asthma patients and 50 normal controls from an Iranian population, and demonstrated an association between IL-4 589 C/T and asthma. Kamali-Sarvestani et al. (2007) also confirmed this polymorphism to be associated with this disease in a southern Iranian population. In addition, Li et al. (2008) performed a meta-analysis showing that this sequence variation plays an important role in asthma pathogenesis, although the authors suggested that further work is needed to confirm the mechanism responsible.

In conclusion, we suggest that the RR genotype of the IL-4R 576 Q/R variant may increase risk of asthma, and in exerting this effect, demonstrates a significant interaction with environments associated with smoking and pets. Further studies with large sample sizes are greatly needed to confirm the relationship between IL-4 genetic polymorphisms and asthma pathogenesis.