Gene–Environment Interaction Between Interleukin-4 Promoter and Molds in Childhood Asthma
Introduction
Asthma is the most common chronic childhood disease (1). It is characterized by recurrent respiratory symptoms, reversible airway obstruction, airway inflammation, and increased airway responsiveness (2). One of the most important pathways on development of asthma involves immunoglobulin (Ig)E antibody responses to ubiquitous allergens. Interleukin (IL)-4 plays an important role in IgE synthesis by activating the pre-T helper cells that trigger isotype switching from IgM/IgG to IgE in B cells by promoting T helper 2 cell development (3). It is reasonable to expect that increase expression of IL-4 might lead to the development of asthma; therefore, the IL-4 promoter region (chromosome 5q31) seems to be the most likely site for polymorphisms. One of the IL-4 promoter polymorphisms -589C/T (also referred to rs number 2243250) is close to the glucocorticoid response element that positively stimulates IL-4 expression (4). Few studies of genetic epidemiology have assessed the relation between IL-4 promoter and childhood asthma in different populations, but these studies provided inconsistent results 5, 6, 7, 8.
In our systematic Medline search, we identified only two previous longitudinal studies 9, 10 and a population-based incident case-control study (11) that investigated exposure before the onset of asthma in children. All the three studies report that children exposure to dampness problems and molds increase the incidence of asthma 9, 10, 11. However, potential modification of the association between exposure to molds and the development of asthma by IL-4 promoter (gene–environment interaction) has not yet been investigated.
We conducted a cohort based, incident, case-control study to assess the independent and joint effect of IL-4 promoter and molds exposure on the risk of childhood asthma.
Section snippets
Data Collection and Study Design
The source population included 44,000 children born in Taoyuan City between January 1, 1995, and December 31, 2002. Taoyuan is an urban–suburban municipality located across the northwestern boarder of Taiwan. In the October 2002 baseline survey, a modified Chinese version of The International Study of Asthma and Allergies in Childhood questionnaire was used to collect information on children’s health, environmental exposures, and other relevant factors. The parents or other guardians were asked
Characteristics of Case and Control Subjects
Table 1 compares the demographic and environmental characteristics between the case and control subjects at baseline. The case subjects had lower duration of breastfeeding, more time spent outdoors, and a greater proportion of parental atopy compared with the control subjects, and were more commonly exposed to cockroaches (94.7% vs. 90.2%) and furry or feathery pets (30.3% vs. 27.1%) in the home.
Independent Effects of IL-4 Promoter and Exposure to Dampness and Mold Problems
Hardy–Weinberg equilibrium tests showed nonsignificance (P > .05) in both case and control groups.
Discussion
We found approximately 43%, 61%, and 50% increased risk developing asthma for children living in homes with any mold problem, mold odor, or visible mold, respectively. Although the IL-4 promoter did not predict asthma, the results indicate that the joint effect of IL-4 promoter, representing genetic constitution, and exposure to visible mold and mold odor was stronger than expected on the basis of their independent effects in additive and multiplicative scales.
Conclusion
Our results are consistent with the hypothesis that molds play an important role in childhood asthma. The results also provide further evidence that IL-4 promoter may influence sensitivity to molds on the development of asthma.
Acknowledgments
This study was supported by the National Science Council (NSC# 99-2314-B-039-021-MY3) and China Medical University (CMU#100-AWARD-07). The authors thank all the field workers who supported data collection, the school administrators and teachers, and especially the parents and children who participated in this study.
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2020, Clinics in Chest MedicineCitation Excerpt :One unique study evaluated the effect of moving children from a high ERMI home environment to a low ERMI forest environment for a few days, and noted improved lung function in the children.168 Much like gene-by-environmental interactions with bacterial exposure, there have been data demonstrating asthma rates linked to a specific polymorphism of the interleukin-4 promoter and visible mold exposure.169 Chronic obstructive lung disease, known as COPD, is an adult pulmonary disease characterized by progressive airway inflammation, usually associated with tobacco inhalation.170
Environmental Contributions to Respiratory Disease in Children
2019, Kendig's Disorders of the Respiratory Tract in ChildrenThe interleukin-4 -589C/T polymorphism and the risk of asthma: A meta-analysis including 7345 cases and 7819 controls
2013, GeneCitation Excerpt :Two articles (Baye et al., 2011; Donfack et al., 2005) reported two cohorts and two articles (Basehore et al., 2004; Zhang et al., 2005) reported three cohorts, each cohort was considered as a separate case–control study. Finally, a total of 40 case–control studies in 34 articles were identified met our inclusion criteria (Adjers et al., 2005; Amirzargar et al., 2009; Attab et al., 2008; Basehore et al., 2004; Battle et al., 2007; Baye et al., 2011; Beghe et al., 2010; Chiang et al., 2007; Cui et al., 2003; Daley et al., 2009; Daneshmandi et al., 2011; de Faria et al., 2008; Donfack et al., 2005; Gervaziev et al., 2006; Hákonarson et al., 2001; Haller et al., 2009; Hijazi and Haider, 2000; Hosseini-Farahabadi et al., 2007; Huang et al., 2012; Hwang et al., 2012; Jiang et al., 2009; Kabesch et al., 2006; Kamali-Sarvestani et al., 2007; Lee et al., 2004; Mak et al., 2007; Park et al., 2004; Rad et al., 2010; Sandford et al., 2000; Schubert et al., 2006; Takabayashi et al., 2000; Trajkov et al., 2008; Walley and Cookson, 1996; Wang et al., 2004; Wu et al., 2010). There were 14 studies of Asians, 15 studies of Caucasians, 4 studies of African American, and 5 studies of other ethnicities.
Association between the interleukin-4 gene C-589T and C+33T polymorphisms and asthma risk: A meta-analysis
2013, Archives of Medical ResearchCitation Excerpt :Although the exact mechanisms by which the IL-4 C+33T polymorphism regulates the expression of the IL-4 gene are still unclear, it has been hypothesized that the variant may affect the efficiency of either transcription or translation of the IL-4 gene, as well as the stability of mRNA, considering the 5′ UTR may contain many gene regulatory elements. To date, a large number of genetic epidemiological studies have examined the association between the IL-4 C-589T and/or C+33T polymorphisms and asthma susceptibility in ethnically diverse populations (14–49). However, consistent results were unavailable.
Gene-environment interactions in asthma and allergic diseases: Challenges and perspectives
2012, Journal of Allergy and Clinical ImmunologyCitation Excerpt :In an attempt to illustrate the current issues in an unbiased way, we performed a literature search for articles published in 2011 or 2012, combining 2 bibliographic sources: (1) Hugenet57 (with “asthma” as the key word in the curated category “gene-environment interaction”), which retrieved 277 articles published since 2001, 80 of which appeared in 2011-2012, and (2) PubMed (search with “asthma AND gene AND environment AND interaction”), which retrieved 150 articles, 49 of which were published in 2011-2012. Table II20,40,43,44,58-64 summarizes key aspects of the 11 articles present in both sources. These 11 articles cover all continents and were published in 10 different journals.