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Effect of early-life antibiotic exposure and IL-13 polymorphism (rs20541) on atopic

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초기 지속성 아토피 피부염에 대한 조기 항생제 노출과 IL-13 다형성 간의 상호작용의 영향. 최근 아토피성 피부염의 발병기전을 이해하기 위한 위생가설이 제기되고 있으며, 그 중에서도 항생제가 미생물을 통해 아토피성 피부염의 발생에 영향을 미친다는 보고가 있다. 따라서 본 연구에서는 생후 6개월 이내의 항생제 노출이 항생제의 수를 고려하여 아토피 피부염의 발생률, 표현형 및 중증도에 미치는 영향을 알아보고자 하였다.

최근 IL-13 프로모터 부위의 유전적 다형성과 아토피성 피부염의 발생에 대한 다양한 연구가 보고되고 있다. 아토피 피부염의 중증도는 SCORAD를 이용하여 아토피 피부염 병변의 정도와 정도를 조사하였고, 항생제 노출, IL-13 유전자 다형성(rs20541)과 이 두 인자의 상호작용을 분석하였다. 다항 로지스틱 회귀 모델을 사용하여 아토피성 피부염 표현형에 대한 초기 항생제 노출, 유전적 다형성 및 둘 사이의 상호작용의 영향을 조사했습니다.

아토피성 피부염으로 진단되었고, 항생제 노출에 따라 중증도가 증가하였다. 아토피 피부염 환자에 대한 생후 6개월의 항생제 노출에 따른 각 시점의 SCORAD 점수. IL-13(rs20541) 다형성에 기반한 각 시점의 아토피 피부염 환자에 대한 SCORAD 점수.

Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age and IL-13(rs20541) genetic variation with the atopic dermatitis phenotypes.

Study population

Ethics Statement

DNA Collection and SNP Genotyping

Physician's assessment of AD and antibiotics exposure

Outcomes

Statistical analysis

To assess effect modification according to IL-13 polymorphisms and antibiotic exposure in early life, subjects were divided into 4 groups based on environmental factors (antibiotic use within 6 months for more than 3 days) and genetic background (genotypes) and multivariable logistic regression models were performed with the data to estimate adjusted odd ratios (aOR) and the corresponding 95% confidence intervals (95% CI) for a comparison of the occurrence of AD by relevant covariates after adjustment for possible confounders: sex, maternal education level , family history of allergic diseases, history of breastfeeding and mode of delivery. Multinomial logistic regression analysis was also used to identify the effects of antibiotic use within 6 months of age and the combined effect of antibiotic use and IL-13 genetic variations on AD phenotypes. Finally, we tested for trends regarding the effect of the risk factors (early life environmental factors and genetic polymorphisms) on the development of AD by two-factor analysis of variance (two-way ANOVA).

Children diagnosed with AD at 1 year accounted for 25.3% of subjects, with a higher proportion of boys compared to non-AD children.

Table 1. Demographic characteristics of the study population
Table 1. Demographic characteristics of the study population

Association between antibiotics exposure within 6 months of age and AD

Forest plot showing the adjusted odds ratio (95% confidence interval) for the association of the incidence of atopic dermatitis at 6 months and 1 to 3 years of age with antibiotic exposure within the first 6 months of age. Forest plot showing the adjusted odds ratio for the association of the incidence of atopic dermatitis with the antibiotic dose-response effect within 6 months. Children who were never exposed to antibiotics are represented by square symbols (Ref.), those who were exposed to antibiotics once are represented by circle symbols, those who were exposed to antibiotics two to three times are represented by triangle symbols, and those who were exposed to antibiotics. to antibiotics more than four times are represented by diamond symbols.. 3) Association between exposure to antibiotics within 6 months of age and AD phenotypes.

Figure  1.  Forest  plot  showing  the  adjusted  odds  ratio  (95%  confidence  interval)  for  association  of  incidence of atopic dermatitis at the age of 6 months and 1 to 3 years with antibiotic exposure within  the first 6 months of age.
Figure 1. Forest plot showing the adjusted odds ratio (95% confidence interval) for association of incidence of atopic dermatitis at the age of 6 months and 1 to 3 years with antibiotic exposure within the first 6 months of age.

Association between antibiotic exposure within 6 months of age and AD phenotypes -11

Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age with the phenotypes of atopic dermatitis. Values ​​are presented as aOR (95% CI) of multinomial logistic regression models, related to non-AD. Adjusted for gender, maternal education, family history of allergic disease, breastfeeding, mode of delivery P<0.05 calculated by multinomial logistic regression analysis.

In contrast, when antibiotic exposure did not occur, AD severity at 1 year was mostly mild, accounting for 82.5% of cases (Table 3, p<0.01). The mean SCORAD score was 9.42 (SD = 10.00) in 1-year-old AD children who were exposed to antibiotics, which was significantly higher than that of AD patients who had no antibiotic exposure within the first 6 months of life (p =0.02). Data were expressed as number and mean with standard deviation (SD) of the estimated mean.

Table 2. Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age with the atopic dermatitis phenotypes
Table 2. Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age with the atopic dermatitis phenotypes

Association between IL-13 gene polymorphism and AD

Association between IL-13 gene polymorphism and phenotypes and severity of AD

Multinomial logistic regression model for the association of IL-13(rs20541) genetic variation with the atopic dermatitis phenotypes. Adjusted for sex, maternal education, family history of allergic disease, breastfeeding, mode of delivery P<0.05 calculated by multinomial logistic regression analysis.

Table 6. SCORAD score for atopic dermatitis patients at each time point based on the IL-13 (rs20541) polymorphism
Table 6. SCORAD score for atopic dermatitis patients at each time point based on the IL-13 (rs20541) polymorphism

Combined effects of IL-13 gene polymorphism and antibiotic exposure within 6 months

Combined effects of IL-13(rs20541) genetic variation and exposure to antibiotics within 6 months of age on the development of atopic dermatitis. P<0.05, Statistically significant differences were determined using a two-way analysis of variance to examine the effects of IL-13 genetic variation and/or antibiotics within 6 months of age and/or interaction. Adjusted odds ratio (95% confidence interval) for development of atopic dermatitis in children with (A) IL-13 (rs20541) GG genotype or (B) GA+AA genotype according to frequency of antibiotic exposure.

Children who have never been exposed to antibiotics are represented by square symbols (Ref.), children who have been exposed to antibiotics once are represented by circle symbols, and those who have been exposed to antibiotics more than twice are represented by triangle symbols. ) Association between antibiotic exposure within 6 months of age and IL-13 gene polymorphism on AD phenotypes.

Table 7. Combined effects of IL-13 (rs20541) genetic variation and exposure to antibiotics within 6 months of age on the development of atopic dermatitis
Table 7. Combined effects of IL-13 (rs20541) genetic variation and exposure to antibiotics within 6 months of age on the development of atopic dermatitis

Association between antibiotic exposure within 6 months of age and IL-13 gene

Association between combined effects of IL-13 gene polymorphism and antibiotic exposure within 6 months of age and severity of AD. We investigated whether there is a combined effect of IL-13 gene polymorphism and antibiotic exposure within the first 6 months of age on the severity of AD. SCORAD scores of patients with atopic dermatitis at each time point based on the antibiotic exposure and IL-13 (rs20541) polymorphism.

This prospective birth cohort study found that the majority of children who were at risk for developing AD, particularly the early AD phenotype, had antibiotic exposure within 6 months of life, which occurred in a dose-dependent manner. dose. Furthermore, the relationship between antibiotic exposure and the development and persistence of AD may be modified by IL-13 genetic susceptibility. These findings suggest that early exposure to antibiotics to some extent contributes to AD development and phenotype, particularly in susceptible infants, and this may be modified by efforts toward primary prevention.

Although exposure to antibiotics in early life is a plausible risk factor for the development of AD in children, existing epidemiological evidence is controversial. Further studies regarding skin barrier disruption, microbiome and metabolites induced during early life antibiotic exposure are needed to support a plausible biological pathway. In addition, this study assessed the effects of antibiotic exposure in the first 6 months of life, focusing on not only the incidence but also the severity and persistence of childhood AD, raising awareness of the prescription of.

Further studies are needed to confirm the causal relationship and prove the mechanism by which antibiotic exposure at a young age causes changes in the skin or gut microbiome and leads to the development of AD. Furthermore, acute bronchiolitis, one of the main causes of antibiotic exposure in early life, is a long-term risk factor for asthma; therefore, frequent bronchiolitis may be related to predisposition to allergy. In conclusion, our birth cohort study suggested that exposure to antibiotics early in life was at risk of developing AD in young children, and the risk increased as the number of antibiotic prescriptions increased.

We also demonstrated that IL-13 (rs20541) genetic polymorphisms significantly affect AD risk, and interactions between IL-13 (rs20541) and early-life antibiotic exposure with dose-response relationships may play a role in the development of AD in early childhood. especially in the early phenotype of AD. Although early life exposure to antibiotics is a potential risk factor for developing AD in children, controversy remains as to whether early exposure to antibiotics is a risk factor in their development of AD. No other study has analyzed the severity and natural course of AD according to the frequency of early antibiotic exposure in children.

Therefore, in this prospective birth cohort study, we focused on the relationship between the development of Alzheimer's disease and antibiotic exposure within 6 months, a critical period in microbiome and immune system development, and further investigated whether the frequency of antibiotic exposure different is associated with severity as well as phenotypes of AD. Pediatric allergists assessed the presence of AD at each visit and obtained the information on antibiotic exposure for more than 3 days.

Table 8. Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age and IL-13 (rs20541) genetic variation with  the atopic dermatitis phenotypes.
Table 8. Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age and IL-13 (rs20541) genetic variation with the atopic dermatitis phenotypes.

수치

Table 1. Demographic characteristics of the study population
Figure  1.  Forest  plot  showing  the  adjusted  odds  ratio  (95%  confidence  interval)  for  association  of  incidence of atopic dermatitis at the age of 6 months and 1 to 3 years with antibiotic exposure within  the first 6 months of age.
Figure 2. Forest plot showing the adjusted odds ratio for association of incidence of atopic dermatitis  with  antibiotic  dose–response  effect  within  6  months  of  age
Table 2. Multinomial logistic regression model for the association of antibiotic exposure within 6 months of age with the atopic dermatitis phenotypes
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