Breastfeeding Might Have Protective Effects on Atopy in Children With the CD14C-159T CT/CC Genotype

Breastfeeding is widely recommended to reduce the risk of sensitization, eczema, and asthma.1 However, the role of breastfeeding in the prevention of allergic diseases is uncertain, with some studies reporting favorable outcomes associated with breastfeeding and others reporting no effects. Cluster of differentiation 14 (CD14) is a well-established susceptibility gene for atopic sensitization,2 but it has demonstrated inconsistent results in its relationship with atopy and breastfeeding.

CD14C-159T is the promoter region of the CD14 gene. Previous genetic studies have indicated that CD14C-159T polymorphisms might interact with environmental factors and contribute to the development of atopy and allergic diseases.3 Although the mechanisms of gene-environmental factor interactions are largely unknown, a polymorphism in the promoter region of a gene might exert its effect by modulating gene expression.4 Recent reports have shown that the effect of breastfeeding on food sensitization can be modified by single nucleotide polymorphisms in the IL-12 receptor β1, toll-like receptor 9, and thymic stromal lymphopoietin receptor genes.5 However, to date there is no evidence that the effect of breastfeeding on sensitization to aeroallergens is modulated by the CD14C-159T genotype. Therefore, we investigated whether the relationship between breastfeeding and sensitization to aeroallergens is modified by the CD14 genotype.

We distributed questionnaires pertaining to breastfeeding to the homes of 1,828 schoolchildren aged 9-12 years from 10 elementary schools in urban (Seoul) and rural areas (Jeongeup) of Korea. Of the 1,828 potential subjects, 1,749 (95.7%) returned the questionnaires. Demographics and information on whether the child breastfed and for how long were obtained through the following questions: "Did you breastfeed your child?" and "How long did you breastfeed?". A breastfed child was defined as having been breastfed for ≥4 months. Skin prick tests for 12 aeroallergens were performed: Dermatophagoides pteronyssinus (D. pteronyssinus [D.p]), Dermatophagoides farinae (D. farinae [D.f]), dog epithelium, cat epithelium, cockroach, grass, mixed tree pollen -1 and -2, alternaria, aspergillus, ragweed, and mugwort. Atopy was defined as a positive skin reaction (wheal diameter, ≥3 mm after subtraction of a negative control). Genotyping of the CD14 polymorphism (-159C/T, rs2569190) was performed using the TaqMan fluorogenic 5' nuclease assay (ABI, Foster City, CA, USA). Genotyping was performed on 1,227 (67%) schoolchildren for whom parental consent for genetic studies was obtained.

The study was approved by the human ethics committees of Hallym University and Ulsan University. Written informed consent was obtained from the parents of all children.

Data were categorized and analyzed using SPSS version 14.0 (SPSS, Inc., Chicago, IL, USA). Multivariate models evaluating the effects of breastfeeding and genetic factors on atopy were adjusted for predefined covariates, including sex, age, place of residence, parental history of allergic disease, income, and body mass index. A P value of less than 0.05 was considered significant.

We analyzed data from 506 atopic children and 721 nonatopic children (Table 1). Overall, schoolchildren who had been breastfed were less likely to be sensitized to aeroallergens (adjusted odds ratio [aOR], 0.712; 95% confidence interval [CI]: 0.555-0.914). This effect was greatest in children breastfed for more than 4 months (aOR, 0.731; 95% CI: 0.555-0.962). There was no significant association between the CD14C-159T genotype and sensitization to aeroallergens. Breastfeeding was associated with a decreased risk of sensitization to aeroallergens in children with the CT/CC genotype (aOR, 0.667; 95% CI: 0.463-0.960) (Table 2).

Table 1
Subject characteristics

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Table 2
Relationship between CD14 genotype and breastfeeding with regard to sensitization to aeroallergens

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To the best of our knowledge, this is the first study to show that the effect of breastfeeding on sensitization to aeroallergens varies according to the CD14C-159T polymorphism. Our results show that breastfeeding might have protective effects on sensitization to aeroallergens in children carrying the CD14C-159T CT/CC genotype.

Reduced soluble CD14 (sCD14) levels in breast milk have been associated with the development of atopy in 4-year-old children.6 The CD14C-159T promoter genotype may alter gene transcription, thereby affecting sCD14 levels.7 T allele homozygotes had higher circulating levels of sCD14 at baseline. However, following an inhalational challenge with low-dose endotoxin,8 the levels of sCD14 increased more in individuals with the C allele, such that there was no difference in sCD14 levels between genotype groups after the challenge. This suggests that carriers of the C allele are more responsive than T allele homozygotes to endotoxin exposure. Therefore, it is possible that carriers of the C allele may react more effectively to breastfeeding.

The association between breastfeeding and sensitization to aeroallergens in childhood may vary significantly depending on the CD14C-159T genotype. Although our study included objective measurements such as genotyping and sensitization, the limitations of cross-sectional studies in elucidating biologic mechanisms are well recognized. Nevertheless, our results support the need for further investigation into the gene-environment interaction of the CD14C-159T polymorphism and breastfeeding in relation to aeroallergen sensitization.