Ann Allergy Asthma Immunol 113 (2014) 160e165
Contents lists available at ScienceDirect
Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents Song-I. Yang, MD *; Eun Lee, MD *; Young-Ho Jung, MD *; Hyung Young Kim, MD y; Ju-Hee Seo, MD z; Ji-Won Kwon, MD x; Byoung-Ju Kim, MD, PhD {; Hyo-Bin Kim, MD, PhD jj; So-Yeon Lee, MD, PhD #; Gwang Cheon Jang, MD, PhD **; Woo-Kyung Kim, MD, PhD yy; Jung Yeon Shim, MD, PhD zz; Mi-Jin Kang, MS xx; Ho-Sung Yu, MS xx; and Soo-Jong Hong, MD, PhD * * Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea y Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Korea z Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea x Department of Pediatrics, Seoul National University Bundang Hospital, Seungnam, Korea { Department of Pediatrics, Inje University Haeundae Paik Hospital, Busan, Korea jj Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea # Department of Pediatrics, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea ** Department of Pediatrics, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea yy Department of Pediatrics and the Allergy and Respiratory Research Laboratory, Inje University Seoul Paik Hospital, Seoul, Korea zz Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea xx Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
A R T I C L E
I N F O
Article history: Received for publication April 1, 2014. Received in revised form April 29, 2014. Accepted for publication May 21, 2014.
A B S T R A C T
Background: Antibiotic use in infancy induces alteration in intestinal microbiota and is associated with the development of allergic diseases. Mold exposure is also associated with allergic diseases. Genetic susceptibility may interact with specific environmental factors in allergic disease development. Objective: To investigate independent and combined effects of antibiotic use and mold exposure in infancy on the risk of allergic rhinitis (AR) in adolescents. Methods: Data on AR and environmental factors were collected using the International Study of Asthma and Allergies in Childhood questionnaire from 7,389 adolescents from Seoul, Korea. TaqMan genotyping was performed for interleukin 13 (IL-13) (rs20541) and Toll-like receptor 4 (rs1927911) polymorphisms in 1,395 adolescents. Results: Age, parental history of AR, antibiotic use in infancy, and pet ownership during pregnancy or infancy were associated with an increased risk of current AR (diagnosis of AR and symptoms of AR within the preceding 12 months). Having older siblings was a protective effect. The adjusted odds ratio (aOR) for current AR for combined antibiotic use and mold exposure in infancy was 1.45 (95% confidence interval [CI], 1.01e2.09). For each factor separately, aORs were 1.25 (95% CI, 1.04e1.50) and 0.99 (95% CI, 0.75e1.31), respectively. Antibiotic and mold exposure in infancy, GA or AA genotypes of IL-13 (rs20541) (aOR 4.53; 95% CI, 1.66e12.38; P for interaction ¼ .05), and CTþTT genotype of Toll-like receptor 4 (rs1927911) (aOR, 3.20; 95% CI, 1.24e8.26; P for interaction ¼ .18) increased the risk of current AR. Conclusion: Antibiotic use and mold exposure in infancy have additive effects on the risk of current AR in genetically susceptible adolescents. Gene-environment interactions between IL-13 (rs20541) and antibiotics or mold may play a role in AR. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Reprints: Soo-Jong Hong, MD, PhD, Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea; E-mail: sjhong@ amc.seoul.kr. Disclosures: Authors have nothing to disclose. Funding: This research was supported by grant A092076 from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea.
Introduction The prevalence of allergic rhinitis (AR) is variable, and the incidence peaks in childhood and adolescence in European and other urban populations.1,2 AR affects individual quality of life and increases socioeconomic burden in terms of overall health care use and costs.1 Several studies suggest that many environmental and
http://dx.doi.org/10.1016/j.anai.2014.05.019 1081-1206/Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
S.-I. Yang et al. / Ann Allergy Asthma Immunol 113 (2014) 160e165
genetic factors influence the development of AR.2e5 However, the roles of these factors are inconsistent and not fully understood. This inconsistency might be related to differences in study populations, environmental exposure factors, and their interactions. Intestinal microbiota may play a role in the maturation of the immune system and the development of allergic diseases, particularly during infancy.6 Experimental studies report that antibiotic use is associated with altered intestinal flora, TH2-polarized immune deviation, and allergic airway disease.7e9 Epidemiologic studies have also identified a correlation between early antibiotic use in children and subsequent diagnosis of AR.10,11 Early-life mold exposure has been associated with a higher prevalence of AR in children in certain urban populations.2,3,12 Mold exposure may interact with other environmental or genetic factors. Interleukin 13 (IL-13) is an important TH2 cytokine involved in the IgE pathway, eosinophilic inflammation, and airway hyperresponsiveness.13 A number of epidemiologic studies report that IL-13 (rs20541) is associated with AR.5,14,15 In a recent Korean epidemiologic study, mold exposure during the first year of life in the setting of a specific IL-13 (rs20541) polymorphism was associated with an increased rate of diagnosis of AR in childhood.2 One murine model demonstrated that mold exposure after antibiotic administration could predispose a host to allergic airway disease and that IL-13 was required for the airway allergic response.16,17 Toll-like receptors (TLRs) are also key molecules in innate and adaptive immunity. Among them, TLR4 interacts with lipopolysaccharides to increase TH1 celleactivating cytokines and activation of T-regulatory cells. The association between TLR4 (rs1927911) and allergic diseases has been found in several studies.18e21 To date, the role of interaction between antibiotic use and mold exposure in infancy on the risk of childhood AR and the modification of their interaction on AR by genetic polymorphisms have not been examined. We hypothesized that antibiotic use and mold exposure in infancy could have a combined effect on the risk of AR, especially in children with certain genetic polymorphisms of IL-13 and TLR4. This study aimed to evaluate the independent and combined effects of antibiotic use and mold exposure in infancy on the risk of AR in Korean middle school children. Associations between antibiotic use or mold exposure as an environmental factor and IL-13 (rs20541) and TLR4 (rs1927911) polymorphisms as genetic factors in childhood AR were investigated.
161
name, sex, date of birth, height, and weight; (2) history of symptoms related to AR; and (3) exposure to environmental factors associated with allergic diseases. Rhinitis was defined as symptoms of sneezing, runny nose, or nasal stuffiness, distinct from respiratory infections. Current AR was defined as physician-diagnosed AR at any point in the child’s lifetime and having nasal symptoms at any time during the 12 months preceding study enrollment. The children’s parents or guardians were asked about antibiotic use and mold exposure in infancy as follows: “In the first 12 months of life, did your child have any antibiotics for more than 3 days?” and “Were visible molds seen in your house during the first 12 months of your child’s life?” Genotyping Genotyping of the IL-13 (rs20541) and TLR4 (rs1927911) polymorphisms was conducted using a TaqMan assay (ABI, Foster City, California). The final volume of polymerase chain reaction was 5 mL, containing 10 ng of genomic DNA and 2.5 mL of TaqMan Universal PCR Master Mix, with 0.13 mL of 40 Assay Mix. Thermal cycle conditions were as follows: 50 C for 2 minutes to activate the uracil N-glycosylase and to prevent carryover contamination, 95 C for 10 minutes to activate the DNA polymerase, followed by 45 cycles of 95 C for 15 seconds and 60 C for 1 minute. All polymerase chain reactions were performed using 384-well plates by a 384-Well Veriti thermal cycler (ABI), and the end point fluorescent readings were performed on an ABI PRISM 7900 HT Sequence Detection System (ABI). Duplicate samples and negative controls were included to ensure accuracy of genotyping. Statistical Analysis The association between current AR and environmental factors were analyzed with multivariate logistic regression analysis and expressed by odds ratios (ORs) with their 95% confidence intervals (CIs). Adjustments were made for potential confounding factors, namely, age, sex, body mass index, parental history of AR, individual school, and household income. All statistical analyses were performed with SPSS statistical software, version 18.0 (SPSS Inc, Chicago, Illinois), with P < .05 considered statistically significant. Results Study Population Characteristics
Methods Study Population A total of 7,389 students were recruited from 8 middle schools in Seoul, Korea. In 2 schools, 1,395 students were selected at random for blood sampling for genotyping. No significant differences were found in the following demographic variables between genotyped and nongenotyped individuals: age, sex, body mass index, parental history of AR, individual schools, and household income (data not shown). The IL-13 (rs20541) and TLR4 (rs1957911) polymorphisms were selected based on previous studies reporting that these single-nucleotide polymorphisms had significant associations with allergic diseases.2,21 The parents or guardians of each participating student provided written informed consent at study entry. The study was approved by the institutional review board of Asan Medical Center, Ulsan University, Seoul, Korea. Questionnaire The International Study of Asthma and Allergies in Childhood written questionnaire was used for this study.22 The parents or guardians of the study participants completed the questionnaires. The questionnaire consists of (1) general characteristics, including
The characteristics of the study population are presented in Table 1. The study population consisted of 3,213 boys and 4,073 girls, with a mean (SD) age of 13.9 (0.9) years. Among them, 30.3% used antibiotics and 10.3% were exposed to mold in infancy. The prevalence of a parental history of AR was 32.8%. The frequencies of the IL-13 (rs20541) GAþAA and TLR4 (rs1927911) CTþTT genotypes were 52.3% and 64.1%, respectively. The distributions of the 2 polymorphisms were in Hardy-Weinberg equilibrium. Prevalence of AR in Korean Children The prevalence of AR was as follows: lifetime symptoms, 38.7%; symptoms in the 12 months preceding the study, 32.1%; lifetime diagnosis, 27.3%; treatment in the 12 months preceding the study, 15.7%; and current AR, 14.2% (Table 2). Risk Factors for Current AR The independent risk factors for current AR were age (aOR, 1.16; 95% CI, 1.05e1.28), parental history of AR (aOR, 2.37; 95% CI, 1.98e2.83), antibiotic use in infancy (aOR, 1.25; 95% CI, 1.04e1.50), and pet ownership during pregnancy or infancy (aOR, 1.73; 95% CI, 1.14e2.63). Having older siblings lowered the risk of current AR (aOR, 0.72; 95% CI, 0.60e0.86) (Table 3). IL-13 (rs20541) or TLR4
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Table 1 Characteristics of the study population
Table 3 Risk factors for current allergic rhinitis in Korean children
Characteristic
No. (%) of study participants (N ¼ 7,389)a
Age, mean (SD), y Male/female sex BMI, mean (SD) School area Downtown Northeastern Northwestern Southeastern Southwestern Parental history of allergic diseases Parental history of asthma Parental history of allergic rhinitis Parental history of atopic dermatitis Household income (10,000 won) Low (299) Middle (300e499) High (500) Cesarean section delivery Breast milk feeding Antibiotic use in infancy Passive smoking Having older siblings Day care attendance Pet ownership during pregnancy or infancy Mold exposure during infancy IL-13 (rs20541) GAþAA genotype TLR4 (rs1927911) CTþTT genotype
13.9 (0.9) 3,213 (44.1)/4,073 (55.9) 19.8 (3.0) 485 (6.6) 2,138 (28.9) 1,687 (22.8) 2,408 (32.6) 671 (9.1) 2,322/5,336 (43.5) 163/3,881 (4.2) 1,552/4,737 (32.8) 302/3,975 (7.6) 1,492/6,260 (23.8) 2,796/6,260 (44.7) 1,972/6,260 (31.5) 2,426/6,532 (37.1) 3,691/6,515 (56.7) 1,947/6,435 (30.3) 4,415/6,979 (63.3) 3,170/7,197 (44.0) 5,380/6,433 (83.6) 205/5,757 (3.6) 638/6,180 (10.3) 729/1,395 (52.3) 894/1,395 (64.1)
Factor
No. (%) of children aOR (95% CI)a
Age Female sex BMI Parental history of allergic rhinitis Household income (10,000 won) Low (299) Middle (300e499) High (500) Cesarean section delivery Breast milk feeding Antibiotic use in infancy Passive smoking Having older siblings Day care attendance Pet ownership during pregnancy or infancy Mold exposure during infancy
3,945 2,281/3,945 (57.8) 3,945 1,281/3,945 (32.5)
1.16 0.84 0.99 2.37
(1.05e1.28)
Contents lists available at ScienceDirect
Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents Song-I. Yang, MD *; Eun Lee, MD *; Young-Ho Jung, MD *; Hyung Young Kim, MD y; Ju-Hee Seo, MD z; Ji-Won Kwon, MD x; Byoung-Ju Kim, MD, PhD {; Hyo-Bin Kim, MD, PhD jj; So-Yeon Lee, MD, PhD #; Gwang Cheon Jang, MD, PhD **; Woo-Kyung Kim, MD, PhD yy; Jung Yeon Shim, MD, PhD zz; Mi-Jin Kang, MS xx; Ho-Sung Yu, MS xx; and Soo-Jong Hong, MD, PhD * * Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea y Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Korea z Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea x Department of Pediatrics, Seoul National University Bundang Hospital, Seungnam, Korea { Department of Pediatrics, Inje University Haeundae Paik Hospital, Busan, Korea jj Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea # Department of Pediatrics, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea ** Department of Pediatrics, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea yy Department of Pediatrics and the Allergy and Respiratory Research Laboratory, Inje University Seoul Paik Hospital, Seoul, Korea zz Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea xx Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
A R T I C L E
I N F O
Article history: Received for publication April 1, 2014. Received in revised form April 29, 2014. Accepted for publication May 21, 2014.
A B S T R A C T
Background: Antibiotic use in infancy induces alteration in intestinal microbiota and is associated with the development of allergic diseases. Mold exposure is also associated with allergic diseases. Genetic susceptibility may interact with specific environmental factors in allergic disease development. Objective: To investigate independent and combined effects of antibiotic use and mold exposure in infancy on the risk of allergic rhinitis (AR) in adolescents. Methods: Data on AR and environmental factors were collected using the International Study of Asthma and Allergies in Childhood questionnaire from 7,389 adolescents from Seoul, Korea. TaqMan genotyping was performed for interleukin 13 (IL-13) (rs20541) and Toll-like receptor 4 (rs1927911) polymorphisms in 1,395 adolescents. Results: Age, parental history of AR, antibiotic use in infancy, and pet ownership during pregnancy or infancy were associated with an increased risk of current AR (diagnosis of AR and symptoms of AR within the preceding 12 months). Having older siblings was a protective effect. The adjusted odds ratio (aOR) for current AR for combined antibiotic use and mold exposure in infancy was 1.45 (95% confidence interval [CI], 1.01e2.09). For each factor separately, aORs were 1.25 (95% CI, 1.04e1.50) and 0.99 (95% CI, 0.75e1.31), respectively. Antibiotic and mold exposure in infancy, GA or AA genotypes of IL-13 (rs20541) (aOR 4.53; 95% CI, 1.66e12.38; P for interaction ¼ .05), and CTþTT genotype of Toll-like receptor 4 (rs1927911) (aOR, 3.20; 95% CI, 1.24e8.26; P for interaction ¼ .18) increased the risk of current AR. Conclusion: Antibiotic use and mold exposure in infancy have additive effects on the risk of current AR in genetically susceptible adolescents. Gene-environment interactions between IL-13 (rs20541) and antibiotics or mold may play a role in AR. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Reprints: Soo-Jong Hong, MD, PhD, Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea; E-mail: sjhong@ amc.seoul.kr. Disclosures: Authors have nothing to disclose. Funding: This research was supported by grant A092076 from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea.
Introduction The prevalence of allergic rhinitis (AR) is variable, and the incidence peaks in childhood and adolescence in European and other urban populations.1,2 AR affects individual quality of life and increases socioeconomic burden in terms of overall health care use and costs.1 Several studies suggest that many environmental and
http://dx.doi.org/10.1016/j.anai.2014.05.019 1081-1206/Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
S.-I. Yang et al. / Ann Allergy Asthma Immunol 113 (2014) 160e165
genetic factors influence the development of AR.2e5 However, the roles of these factors are inconsistent and not fully understood. This inconsistency might be related to differences in study populations, environmental exposure factors, and their interactions. Intestinal microbiota may play a role in the maturation of the immune system and the development of allergic diseases, particularly during infancy.6 Experimental studies report that antibiotic use is associated with altered intestinal flora, TH2-polarized immune deviation, and allergic airway disease.7e9 Epidemiologic studies have also identified a correlation between early antibiotic use in children and subsequent diagnosis of AR.10,11 Early-life mold exposure has been associated with a higher prevalence of AR in children in certain urban populations.2,3,12 Mold exposure may interact with other environmental or genetic factors. Interleukin 13 (IL-13) is an important TH2 cytokine involved in the IgE pathway, eosinophilic inflammation, and airway hyperresponsiveness.13 A number of epidemiologic studies report that IL-13 (rs20541) is associated with AR.5,14,15 In a recent Korean epidemiologic study, mold exposure during the first year of life in the setting of a specific IL-13 (rs20541) polymorphism was associated with an increased rate of diagnosis of AR in childhood.2 One murine model demonstrated that mold exposure after antibiotic administration could predispose a host to allergic airway disease and that IL-13 was required for the airway allergic response.16,17 Toll-like receptors (TLRs) are also key molecules in innate and adaptive immunity. Among them, TLR4 interacts with lipopolysaccharides to increase TH1 celleactivating cytokines and activation of T-regulatory cells. The association between TLR4 (rs1927911) and allergic diseases has been found in several studies.18e21 To date, the role of interaction between antibiotic use and mold exposure in infancy on the risk of childhood AR and the modification of their interaction on AR by genetic polymorphisms have not been examined. We hypothesized that antibiotic use and mold exposure in infancy could have a combined effect on the risk of AR, especially in children with certain genetic polymorphisms of IL-13 and TLR4. This study aimed to evaluate the independent and combined effects of antibiotic use and mold exposure in infancy on the risk of AR in Korean middle school children. Associations between antibiotic use or mold exposure as an environmental factor and IL-13 (rs20541) and TLR4 (rs1927911) polymorphisms as genetic factors in childhood AR were investigated.
161
name, sex, date of birth, height, and weight; (2) history of symptoms related to AR; and (3) exposure to environmental factors associated with allergic diseases. Rhinitis was defined as symptoms of sneezing, runny nose, or nasal stuffiness, distinct from respiratory infections. Current AR was defined as physician-diagnosed AR at any point in the child’s lifetime and having nasal symptoms at any time during the 12 months preceding study enrollment. The children’s parents or guardians were asked about antibiotic use and mold exposure in infancy as follows: “In the first 12 months of life, did your child have any antibiotics for more than 3 days?” and “Were visible molds seen in your house during the first 12 months of your child’s life?” Genotyping Genotyping of the IL-13 (rs20541) and TLR4 (rs1927911) polymorphisms was conducted using a TaqMan assay (ABI, Foster City, California). The final volume of polymerase chain reaction was 5 mL, containing 10 ng of genomic DNA and 2.5 mL of TaqMan Universal PCR Master Mix, with 0.13 mL of 40 Assay Mix. Thermal cycle conditions were as follows: 50 C for 2 minutes to activate the uracil N-glycosylase and to prevent carryover contamination, 95 C for 10 minutes to activate the DNA polymerase, followed by 45 cycles of 95 C for 15 seconds and 60 C for 1 minute. All polymerase chain reactions were performed using 384-well plates by a 384-Well Veriti thermal cycler (ABI), and the end point fluorescent readings were performed on an ABI PRISM 7900 HT Sequence Detection System (ABI). Duplicate samples and negative controls were included to ensure accuracy of genotyping. Statistical Analysis The association between current AR and environmental factors were analyzed with multivariate logistic regression analysis and expressed by odds ratios (ORs) with their 95% confidence intervals (CIs). Adjustments were made for potential confounding factors, namely, age, sex, body mass index, parental history of AR, individual school, and household income. All statistical analyses were performed with SPSS statistical software, version 18.0 (SPSS Inc, Chicago, Illinois), with P < .05 considered statistically significant. Results Study Population Characteristics
Methods Study Population A total of 7,389 students were recruited from 8 middle schools in Seoul, Korea. In 2 schools, 1,395 students were selected at random for blood sampling for genotyping. No significant differences were found in the following demographic variables between genotyped and nongenotyped individuals: age, sex, body mass index, parental history of AR, individual schools, and household income (data not shown). The IL-13 (rs20541) and TLR4 (rs1957911) polymorphisms were selected based on previous studies reporting that these single-nucleotide polymorphisms had significant associations with allergic diseases.2,21 The parents or guardians of each participating student provided written informed consent at study entry. The study was approved by the institutional review board of Asan Medical Center, Ulsan University, Seoul, Korea. Questionnaire The International Study of Asthma and Allergies in Childhood written questionnaire was used for this study.22 The parents or guardians of the study participants completed the questionnaires. The questionnaire consists of (1) general characteristics, including
The characteristics of the study population are presented in Table 1. The study population consisted of 3,213 boys and 4,073 girls, with a mean (SD) age of 13.9 (0.9) years. Among them, 30.3% used antibiotics and 10.3% were exposed to mold in infancy. The prevalence of a parental history of AR was 32.8%. The frequencies of the IL-13 (rs20541) GAþAA and TLR4 (rs1927911) CTþTT genotypes were 52.3% and 64.1%, respectively. The distributions of the 2 polymorphisms were in Hardy-Weinberg equilibrium. Prevalence of AR in Korean Children The prevalence of AR was as follows: lifetime symptoms, 38.7%; symptoms in the 12 months preceding the study, 32.1%; lifetime diagnosis, 27.3%; treatment in the 12 months preceding the study, 15.7%; and current AR, 14.2% (Table 2). Risk Factors for Current AR The independent risk factors for current AR were age (aOR, 1.16; 95% CI, 1.05e1.28), parental history of AR (aOR, 2.37; 95% CI, 1.98e2.83), antibiotic use in infancy (aOR, 1.25; 95% CI, 1.04e1.50), and pet ownership during pregnancy or infancy (aOR, 1.73; 95% CI, 1.14e2.63). Having older siblings lowered the risk of current AR (aOR, 0.72; 95% CI, 0.60e0.86) (Table 3). IL-13 (rs20541) or TLR4
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S.-I. Yang et al. / Ann Allergy Asthma Immunol 113 (2014) 160e165
Table 1 Characteristics of the study population
Table 3 Risk factors for current allergic rhinitis in Korean children
Characteristic
No. (%) of study participants (N ¼ 7,389)a
Age, mean (SD), y Male/female sex BMI, mean (SD) School area Downtown Northeastern Northwestern Southeastern Southwestern Parental history of allergic diseases Parental history of asthma Parental history of allergic rhinitis Parental history of atopic dermatitis Household income (10,000 won) Low (299) Middle (300e499) High (500) Cesarean section delivery Breast milk feeding Antibiotic use in infancy Passive smoking Having older siblings Day care attendance Pet ownership during pregnancy or infancy Mold exposure during infancy IL-13 (rs20541) GAþAA genotype TLR4 (rs1927911) CTþTT genotype
13.9 (0.9) 3,213 (44.1)/4,073 (55.9) 19.8 (3.0) 485 (6.6) 2,138 (28.9) 1,687 (22.8) 2,408 (32.6) 671 (9.1) 2,322/5,336 (43.5) 163/3,881 (4.2) 1,552/4,737 (32.8) 302/3,975 (7.6) 1,492/6,260 (23.8) 2,796/6,260 (44.7) 1,972/6,260 (31.5) 2,426/6,532 (37.1) 3,691/6,515 (56.7) 1,947/6,435 (30.3) 4,415/6,979 (63.3) 3,170/7,197 (44.0) 5,380/6,433 (83.6) 205/5,757 (3.6) 638/6,180 (10.3) 729/1,395 (52.3) 894/1,395 (64.1)
Factor
No. (%) of children aOR (95% CI)a
Age Female sex BMI Parental history of allergic rhinitis Household income (10,000 won) Low (299) Middle (300e499) High (500) Cesarean section delivery Breast milk feeding Antibiotic use in infancy Passive smoking Having older siblings Day care attendance Pet ownership during pregnancy or infancy Mold exposure during infancy
3,945 2,281/3,945 (57.8) 3,945 1,281/3,945 (32.5)
1.16 0.84 0.99 2.37
(1.05e1.28)
