Elsevier

Annals of Epidemiology

Volume 22, Issue 4, April 2012, Pages 250-256
Annals of Epidemiology

Gene–Environment Interaction Between Interleukin-4 Promoter and Molds in Childhood Asthma

https://doi.org/10.1016/j.annepidem.2012.01.008Get rights and content

Purpose

To assess the role of gene–environment interaction between interleukin (IL)-4 promoter and mold exposure on the development of asthma.

Methods

We conducted a cohort-based, incident, case-control study. The case group consisted of 188 children with new asthma and the control group (n = 376) was matched for age and gender. The outcome of interest was the development of asthma over the 6-year study period. The studied determinants were three polymorphisms of IL-4 promoter (TT, CT, and CC) and three indicators of exposure including histories of water damage, presence of visible molds, and perceived mold odor in the home.

Results

Apparent joint effects between IL-4 promoter and mold exposure were observed on both additive and multiplicative scales. Specially, the risk of asthma was significantly associated with children carrying the CT genotype and visible mold exposure comparing with those carrying the TT genotype without any exposure indicator (adjusted odds ratio [OR], 2.14; 95% confidence interval [CI], 1.05–4.34; modified Rothman synergy index for directly use of odds and OR [s] = 1.41; P for interaction = .03). A similar tendency was found (s = 1.30; P for interaction = .04) for children who were exposed to mold odor and carried CT genotype (adjusted OR, 1.99; 95% CI, 1.03–4.41).

Conclusions

The results of this study suggest that gene–environment interactions between the IL-4 promoter and an indoor mold problem may play an important role 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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