Gene-environment interaction between Toll-like receptor 4 and mold exposure in the development of atopic dermatitis in preschool children

Hyung Young Kim; Young-Ho Jung; Kyungmo Hong; Gwang Cheon Jang; Ju-Hee Seo; Ji-Won Kwon; Byoung-Joo Kim; Hyo Bin Kim; So-Yeon Lee; Dae Jin Song; Woo Kyung Kim; Jung Yeon Shim; Mi-Jin Kang; Young Joon Kim; Ho-Sung Yu; Soo-Jong Hong

doi:10.4168/aard.2013.1.2.129

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Kim, Jung, Hong, Jang, Seo, Kwon, Kim, Kim, Lee, Song, Kim, Shim, Kang, Kim, Yu, and Hong: Gene-environment interaction between Toll-like receptor 4 and mold exposure in the development of atopic dermatitis in preschool children

Original Article

Allergy, Asthma & Respiratory Disease 2013; 1(2): 129-137.

Published online: 27 June 2013

DOI: https://doi.org/10.4168/aard.2013.1.2.129

Gene-environment interaction between Toll-like receptor 4 and mold exposure in the development of atopic dermatitis in preschool children

Hyung Young Kim¹, Young-Ho Jung^2,³, Kyungmo Hong⁴, Gwang Cheon Jang^2,⁵, Ju-Hee Seo⁶, Ji-Won Kwon^2,⁷, Byoung-Joo Kim⁸, Hyo Bin Kim^2,⁹, So-Yeon Lee^2,¹⁰, Dae Jin Song^2,¹¹, Woo Kyung Kim^2,¹²

, Jung Yeon Shim^2,¹³, Mi-Jin Kang¹⁴, Young Joon Kim¹⁴, Ho-Sung Yu¹⁴, Soo-Jong Hong^2,³

¹Department of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea.

²Research Center for Standardization of Allergic Diseases, Asan Medical Center, Seoul, Korea.

³Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

⁴Goucher College, Baltimore, MD, USA.

⁵Department of Pediatrics, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea.

⁶Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea.

⁷Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.

⁸Department of Pediatrics, Inje University Haeundae Paik Hospital, Busan, Korea.

⁹Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea.

¹⁰Department of Pediatrics, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea.

¹¹Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.

¹²Department of Pediatrics, Inje University Seoul Paik Hospital, Seoul, Korea.

¹³Department of Pediatrics, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

¹⁴Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

Correspondence to: Soo-Jong Hong. Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3379, Fax: +82-2-473-3725, sjhong@amc.seoul.kr

Received 6 January 2013 Revised 25 March 2013 Accepted 26 March 2013

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).

Abstract

Purpose

Genetic factors and environmental exposures are recognized as important risk factors for atopic dermatitis (AD) in children. Inflammatory responses by molds can be mediated via Toll-like receptor 4 (TLR4). The aims of this study were to investigate mold as risk factor of AD and gene-environment interaction on AD in preschool children.

Methods

We undertook a cross-sectional survey with 986 preschool children. We investigated five mold exposure measures (dampness stain, dampness damage, visible mold, mold odor, and house repair). The TLR4 polymorphism (rs1927911) was genotyped by TaqMan assay.

Results

The prevalence of AD was as follows: AD diagnosis by questionnaire, 35.1%; current AD (lifetime diagnosis together with symptoms in the last 12 months), 21.5%. When children with parental history of AD were exposed to mold odor during infancy and house repair during the last 12 months, the risk for current AD (adjusted odds ratio [aOR], 6.826; 95% confidence interval [CI], 2.511 to 18.554 vs. aOR, 6.143; 95% CI, 2.348 to 16.074) was further increased than only with parental history of AD. In children with the CC genotype of TLR4 polymorphism, the risk of AD was increased by mold exposure.

Conclusion

This investigation identified that mold exposure is potential risk factor for AD in preschool children. Parental history of AD and mold exposure during infancy and the last 12 months had synergistic effect on high prevalence of AD. We identified that mold exposure and TLR4 polymorphism have an effect on the development of atopic dermatitis.

Keywords: Atopic dermatitis, Mold, Risk factor, Toll-like receptor 4, Polymorphism

INTRODUCTION

Atopic dermatitis (AD) is a genetically determined, chronic, relapsing and highly pruritic inflammatory skin disease frequently associated with the development of allergic rhinitis or asthma.1) The prevalence of AD is increasing in developed countries, including Korea, probably due to changes in lifestyle and the environment.2-5)

The etiology of AD is thought to be associated with diverse factors including personal, genetic and environmental factors. The rapid increase in the prevalence of AD over the last 30 to 40 years suggests that environmental factors rather than genetic effects are responsible for this increased prevalence, although interactions between genetic and environmental factors may also be important.6-8) Recent clinical research has therefore focused on identifying gene-environment interactions that contribute to the development of allergic diseases including AD.4,8-13)

Household moisture and mold are associated with adverse health effects in children,14,15) and mold is considered as a key indoor environmental exposure.16) Previously we reported early life exposure to mold was important risk factor for the development of AD especially in susceptible children.4) Some studies have shown that markers of indoor dampness, such as visible mold and water damage, were associated with increased risk of AD in childhood,17,18) but this association was not found in all studies.6) The relative importance of mold exposure for the development of AD in preschool children remains unexplored.

Immune responsiveness to many microbial pathogens depends on a family of pattern recognition receptors known as Toll-like receptors, which are the major innate recognition system for microbial invaders in vertebrates.19) Toll-like receptor 4 (TLR4) recognizes, and transduces intracellular signals in response to bacterial endotoxin, a major component of the bacterial cell wall of gram-negative bacteria.20) Several studies have shown that TLR4 were related to fungal infection.21,22) Several studies showed the associations that inflammatory responses by molds are mediated via TLR4.23,24) However, it is not known whether interactions between TLR4 and mold have an impact on the development of allergic diseases, including AD.

The purpose of the present study was to investigate mold as risk factor of AD and gene-environment interaction on AD in preschool children.

MATERIALS AND METHODS

1. Subjects and study design

Between July and August 2010, this study recruited 986 preschool children aged 3 to 7 years from 16 kindergartens randomly selected from Seoul, Ilsan, and Gwacheon in Korea. A modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire25) was used to determine the prevalence of symptoms and diagnosis of allergic diseases. Cases in which gender was not reported were excluded, and responses from a total of 933 preschool children and their parents were included in the analyses. Among 933 preschooler, 901 children answered the questions related to current AD. A total of 919 preschool children and their parents responded to the study questionnaires, which represents an overall response rate of 98.5%.

The mean age was 4.87±1.05 years in preschool children included in this survey. The sample included 480 boys and 453 girls (male:female, 51.4:48.6). The prevalence of a parental history of allergic disease (including AD, asthma, and allergic rhinitis) that had been previously diagnosed by a doctor was 49.0% in preschool children. The prevalences of mold exposure in the house during infancy and in the current house were 50.1% and 46.1%, respectively (Table 1).

This study was approved by the Institutional Review Board of Asan Medical Center. Written consent was obtained from all parents and guardians following a detailed explanation of the study.

2. ISAAC questionnaire and SCORing atopic dermatitis index

The modified Korean version of ISAAC was previously validated as a tool for assessing allergic symptoms and diagnosis in Korean children.26) The questionnaire consists of three main sections: 1) general characteristics including names, sex, date of birth, height, and weight; 2) a history of symptoms related to asthma, allergic rhinitis, AD, allergic conjunctivitis and food allergy; and 3) exposure to environmental factors associated with allergic disease. The Korean version of the ISSAC questionnaire was completed by parents or guardians of the preschool children. Association between mold exposure and the development of AD was identified in our previous study.4) So the questionnaires related to mold exposure are subclassified into 5 categories (dampness stain, dampness damage, visible mold, mold odor and house repair due to mold) in this survey in order to identify more correctly the impact of mold exposure.27)

3. White blood cells, eosinophils, total IgE, and specific IgE

White blood cells and the percentage of blood eosinophils were measured. Serum total IgE and specific IgE were measured by fluorescent enzyme immunoassay using the ImmunoCAP system (Phadia AB, Uppsala, Sweden). The specific IgE was measured for seven major inhaled allergens: Dermatophagoides farinae, cat, dog, cockroach, alternaria, mugwort, and alder. The specific IgE was considered to be positive if it was over 0.35 kUA/L.

4. Genotyping

The genotyping of the TLR4 (rs1927911) polymorphism was conducted using a TaqMan assay (ABI, Foster City, CA, USA). The final volume of polymerase chain reaction (PCR) was 5 µL, containing 10 ng of genomic DNA and 2.5 µL TaqMan Universal PCR Master Mix, with 0.13 µL of 40X Assay Mix (Assay ID C_11722141_10) in a 384-well plate.

5. Statistical analysis

Statistic analyses were performed using the IBM SPSS ver. 18.0 (IBM Co., Armonk, NY, USA). Prevalence rates are presented with their 95% confidence interval (CI). Chi-square test and logistic regression analyses were conducted to identify potential risk factors for AD. Age, sex, and body mass index (BMI) were adjusted as personal factors, parental history of AD as a familial factor, the degree of maternal education as a socioeconomic factor, and sensitization of house dust mite as a confounding factor in multivariate analysis. Sensitization of house dust mite means the positivity on skin prick test or ImmunoCAP of house dust mite. For all analyses P value <0.05 was regarded as statistically significant.

RESULTS

1. Prevalence of AD

The prevalence of AD was as follows: lifetime symptoms, 28.0%; symptoms in the last 12 months, 28.7%; lifetime diagnosis by questionnaire, 35.1%; treatment in the last 12 months, 16.6%; current AD (which was defined as lifetime diagnosis by questionnaire together with symptoms in the last 12 months), 21.5% (Table 2). In consideration of natural course of AD in children, current AD can be regarded as proper item for evaluating exactly children with AD. So, we used "current AD" in further statistical analysis.

2. Risk factors for AD

By multivariate logistic regression analyses, possible risk factors for current AD were identified as a parental history of AD and some measures related to mold exposure. In preschool children with current AD, a parental history of AD (adjusted odds ratio [aOR], 3.313; 95% CI, 2.107 to 5.208), three mold measures during infancy (dampness damage [aOR, 1.873; 95% CI, 1.223 to 2.869], mold odor [aOR, 1.740; 95% CI, 1.148 to 2.639], house repair due to mold [aOR, 1.611; 95% CI, 1.060 to 2.448]) and four mold measures during the last 12 months (dampness stain [aOR, 1.579; 95% CI, 1.054 to 2.367], dampness damage [aOR, 1.722; 95% CI, 1.065 to 2.784], mold odor [aOR, 1.733; 95% CI, 1.118 to 2.684], house repair due to mold [aOR, 1.758; 95% CI, 1.128 to 2.742]) were verified as potential risk factors (Table 3). In brief, parental history of AD and mold exposure were potential risk factors for AD in preschool children.

3. Interaction between family history of AD and mold exposure

Analyses were conducted to identify whether an interaction between a hereditary factor (parental history of AD) and environmental exposure (five measures related to mold exposure: dampness stain, dampness damage, visible mold, mold odor, and house repair due to mold in the house) was associated with the occurrence of AD. The study group was divided into four subgroups according to the presence or absence of the environmental and hereditary factors (parental history of AD and the measures of mold exposure).

For a parental history of AD and four mold measures (dampness stain, visible mold, mold odor, and house repair) during infancy, the aOR of current AD increased up to 4.360 (95% CI, 1.949 to 9.755), 4.996 (95% CI, 2.294 to 10.884), 6.826 (95% CI, 2.511 to 18.554) and 4.571 (95% CI, 1.814 to 11.515), respectively (Table 4). For a parental history of AD and five mold measures (dampness stain, dampness damage, visible mold, mold odor, and house repair due to mold) during the last 12 months, the aOR of current AD increased up to 4.622 (95% CI, 1.894 to 11.280), 4.104 (95% CI, 1.144 to 14.717), 3.817 (95% CI, 1.747 to 8.339), 5.512 (95% CI, 2.073 to 14.656) and 6.143 (95% CI, 2.348 to 16.074), respectively (Table 4).

4. Gene-environment interaction between TLR4 (rs1927911) polymorphism and mold exposure

We also identified a relationship between a specific gene and environment effects that is associated with the development of AD. Children with only TLR4 polymorphism have no risk on the development of AD (Table 5). When children with the CC genotype, however, were exposed to mold (dampness damage) during infancy, the development of current AD was increased (aOR, 3.163; 95% CI, 1.485 to 6.738) (Table 6). For the children with the CC genotype and three mold measures (dampness stain, dampness damage, and visible mold) during the last 12 months, the aOR of current AD increased up to 2.372 (95% CI, 1.144 to 4.919), 2.939 (95% CI, 1.250 to 6.910) and 3.561 (95% CI, 1.727 to 7.343), respectively (Table 6).

DISCUSSION

This was the first representative cross-sectional survey identifying the association between AD and mold exposure in preschool children in metropolitan area of Korea.

In the present study, we identified the fact that mold exposure could be significantly relevant to the development of AD. Our results show that children with a hereditary susceptibility to AD, defined as a parental history of AD, were more likely to develop AD when they had a history of exposure to mold. The coexistence of a parental history of AD and factors related to mold exposure, such as mold odor during infancy and house repair during the last 12 months, was synergistically associated with occurence of current AD (aOR, 6.826; 95% CI, 2.511 to 18.554 and aOR, 6.143; 95% CI, 2.348 to 16.074, respectively). It is thought that mold exposure during infancy is very important for the development of AD in susceptible children. Mold exposure during in preschool age, on the other hand, can be a possible cause for occurrence or aggravation of AD in susceptible children.

Some studies show that TLR4 polymorphisms may have a role in the development of Th2-dominant allergic inflammation.28,29) In this study, there was no significant association between the TLR4 (rs1927911) polymorphism and development of AD. However, the risk of AD was increased by mold exposure in children with the CC genotype of TLR4 polymorphism. Even for the relationship between the nonrisk genotype and mold exposure, the present study shows that the risk of developing AD is increased in children who have the specific genotype. It will be important to elucidate the basis of the genetic interaction with mold exposure in future studies. The reason why the effect of TLR4 polymorphism is less than familial history of AD as a hereditary factor: presumably, unknown factors such as other genes except TLR4 or other common environment are regarded as possible explanations.

It was well known that a family history of allergic diseases is associated with the prevalence of AD, suggesting that genetic factors play a central role in the development of childhood AD.4,8,16,30) In the present study, parental history of AD was the only significant familial risk factor for AD in preschool children; parental histories of other allergic diseases such as asthma and allergic rhinitis were not significant.

Molds are important indoor allergens for asthma and allergic rhinitis, and indoor exposure to certain fungal genera such as Aspergillus and Penicillium has been identified as a risk factor for asthma, atopy and respiratory symptoms in children.31) One study reported that molds were unrelated to the prevalence of AD,32) whereas several other studies have reported an increased risk of developing AD associated with mold as home environments.33-36) The mechanisms underlying the association between mold and AD are not known. The skin is an active immunological organ that functions as a primary defense and biosensor to the external environment.37) Skin barrier dysfunction caused by environmental proteases has emerged as a critical driving force in the initiation and exacerbation of AD and the "atopic march" in allergic diseases.38) Mycotoxins are secondary metabolites produced by mold as they grow. Many studies have shown that inhalation of molds and their products (e.g., conidia and mycotoxins) leads to adverse health effects such as allergic and respiratory diseases.39,40) The skin barrier of patients with AD is damaged, which facilitates penetration of allergens such as molds.11) The findings that mold exposure as potential environmental risk factor could interact with hereditary factors and act on the development of AD were verified in this investigation. However, it is still not known exactly how interaction between TLR4 polymorphism and mold affects the development of allergic diseases like AD.

Our study has some limitations. First, this is a cross-sectional study, which does not allow us to establish a true causal relationship and therefore the questionnaire about mold exposure cannot explain entirely whether mold exposure can act on a cause of the first development of AD or a mere aggravation factor of AD in preschool age. So, it is reasonable to assume that mold exposure during the last 12 months may be a aggravation factor rather than a major cause for the development of current AD. Second, the exposure levels of factors related to mold were not quantitatively measured but were based on a questionnaire. It is likely that the questionnaire-based assessment is usual situation in epidemiologic studies and only partially reflects true mold exposure, but there is very rare data of the real measurement of fungus by culture or metagenomics regarding to allergic diseases because of expensive cost. However, by investigating five measures related to mold exposure in detail, we tried to maximize the accuracy of the questionnaire for assessing mold exposure. And the results of each individual questionnaire based measures of mold exposure was consistent effect on the development of AD in this study. Third, the number of children included in this study was relatively small. However, the number of children was greater than 900 and the response rate was comparatively high (98.5%). Fourth, there may be some recall bias in the study. However, in comparison to studies investigating older children, the possibility of recall bias may be low because the subjects were preschool-aged. Fifth, there may be many possibilities of nonmeasured important variables and confounding factors. Although all of variables and confounding factors are not considered in this study, we tried to investigate the fact that mold exposure could affect the development of AD by adjusting the sensitization of house dust mite as representative confounding factor.

The main strengths of the present study include the in-depth study examination of various factors related to mold exposure and the replication of our previous study4) related to gene-environment interactions on the development of AD. These detailed questionnaire based measurements of indoor mold exposure may be used in the future epidemiologic study for the evaluation of environmental factors.

In conclusion, the main focus of the present study was to analyze interactions between genetic and environmental risk factors in the development of AD, especially in susceptible children. Additional experimental studies, such as the direct measurement of mold exposure in a cohort study or an animal study of mold exposure, will be needed to better understand these observations. In addition, we identified a possible gene-environment interaction between TLR4 and mold exposure. These findings suggest that early avoidance of mold exposure during infancy is important to prevent the development of AD, especially in susceptible children.

Figures and Tables

Table 1

Subject characteristics (n=933)

Values are presented as number (%) or mean±standard deviation.

^*Five measures: 1) dampness stain, 2) dampness damage, 3) visible mold, 4) mold odor, and 5) house repair due to mold.

Table 2

Prevalence of atopic dermatitis (AD)

Values are presented as number (%).

^*Lifetime AD diagnosis by questionnaire together with AD symptoms in the last 12 months.

Table 3

Risk factors for atopic dermatitis in preschool children

Data were calculated by logistic regression multivariate analysis.

OR, odds ratio; AD, atopic dermatitis; BMI, body mass index; AR, allergic rhinitis; IgE, immunoglobulin E.

^*OR=adjusted by age, sex, BMI, parental history of atopic dermatitis, and degree of maternal education. ^†OR=adjusted by age, sex, BMI, and degree of maternal education. ^‡OR=adjusted by age, sex, BMI, parental history of atopic dermatitis, degree of maternal education, and sensitization of house dust mite. ^§Lifetime AD diagnosis by questionnaire together with AD symptoms in the last 12 months.

Table 4

Interactions between parental history of atopic dermatitis and mold exposure on the development of current atopic dermatitis

Data were calculated by logistic regression multivariate analysis.

OR, odds ratio; AD, atopic dermatitis.

^*Lifetime AD diagnosis by questionnaire together with AD symptoms in the last 12 months. ^†OR=adjusted by age, sex, body mass index, degree of maternal education, and sensitization of house dust mite.

Table 5

Association analysis between TLR4 (rs1927911) and current atopic dermatitis

Data were calculated by logistic regression multivariate analysis. Data were adjusted by age, sex, body mass index, parental history of atopic dermatitis and degree of maternal education.

TLR4, Toll-like receptor 4; AD, atopic dermatitis; aOR, adjusted odds ratio; CI, confidence interval.

^*Lifetime AD diagnosis by questionnaire together with AD symptoms in the last 12 months.

Table 6

Interactions between TLR4 polymorphism (rs1927911) and mold exposure on the development of current atopic dermatitis

Data were calculated by logistic regression multivariate analysis.

OR, odds ratio; AD, atopic dermatitis; TLR, Toll-like receptor.

^*Lifetime AD diagnosis by questionnaire together with AD symptoms in the last 12 months. ^†OR=adjusted by age, sex, body mass index, parental history of atopic dermatitis, degree of maternal education, and sensitization of house dust mite.

ACKNOWLEDGMENTS

The authors thank the field workers, kindergarten teachers and other staff who supported data collection, and all parents and children who participated in this study. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare, Republic of Korea (A092076).

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ORCID iDs: Woo Kyung Kim
https://orcid.org/http://orcid.org/0000-0001-8730-010X
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