Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Epidemiology and Biostatistics

Sub-Department

Epidemiology

First Advisor

Wilfried Karmaus

Abstract

Background: The role of breast milk components on childhood asthma is controversial. The aims of this prospective study are to determine the relationship of immune markers in maternal serum during gestation and breast milk to asthma-like symptoms (AS) in infancy, and the association between fatty acids (FAs) in colostrum and breast milk with AS and atopy. A second goal is to conduct cluster analyses to obtain different immune marker profiles in serum and in whey in order to estimate the risk of these immune clusters for AS in infancy.

Methods: Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median: 3 weeks before delivery), colostrum and breast milk (two days and three weeks after delivery, respectively) samples were collected. Concentrations of interferon (IFN)-gamma, IFN gamma-induced protein 10 (IP-10 or CXCL10), CCL11, interleukin (IL) 1-beta;, IL-4, IL-5, IL-6, CXCL8, IL-10, IL-12(p70), IL-13, transforming growth factor (TGF)-beta-1, and immunoglobulin (Ig) A in both maternal serum and milk whey were determined via immunoassays. FAs concentrations of n-3 and n-6 were determined by gas chromatography. AS of the infant were ascertained at 6 and 12 months, respectively. Cluster analyses (k-means method) identified different profiles of immune marker. Generalized estimating equations estimated the relative risks (RRs) of repeated measurements of AS related to individual immune markers, fatty acids, and immune clusters, considering intra-individual correlations and adjusting for confounders. To provide comparable risk estimates, I used quartiles of the immune markers, except for IL-5 in whey, which was dichotomized. FAs were dichotomized (high vs. median and low). Children were invited to participate in a clinical exam including a skin prick test to measure allergic sensitization (atopy) against 6 allergens (cat dander, milk, egg, peanut, mix of Dermatophagoides farina and pteroniyssimus, and Alternaria). These data were analyzed using log-binomial models.

Results: Of 178 women, 161 provided blood, 33 colostrum, and 115 breast milk samples. Asthma-like symptoms were ascertained in 140 children, 45 children participated in the clinical exam. Most immune markers in serum and milk whey were moderately or highly correlated; however, IgA was negatively correlated. Infants in the highest quartile of IL-13 in both serum and whey were at a higher risk of AS (RR = 3.02 and 4.18; respectively) compared to infants in the first quartile. High levels of IL-5 in serum and whey were also identified as risk factors for AS. In addition, increased secretory IgA and TGF-beta-1 in breast milk reduced the risks of AS. Regarding FAs, high levels of total n-6 FAs (lipid-based) in breast milk were associated with an increased risk of AS in infants (RR=2.91), even after controlling for total n-3 FAs (RR = 2.07). High levels of total n-3 FAs controlling for n-6 decreased the risk of atopy at age 12 months. Four immune clusters were identified having similar immune profiles within and between clusters. One cluster with higher levels of Th2 cytokines (IL-13, IL-5) and lower levels of IgA and TGF-beta-1 in whey was associated with a higher incidence of repeated AS (RR = 2.62). A maternal serum protein cluster with higher levels of Th2 markers and lower levels of TGF-beta-1 (RR = 2.02) was also linked to AS at ages 6 and 12 months.

Conclusions: Maternal serum and whey levels of IL-5 and IL-13 are risk markers for AS; whey IgA and TGF-beta-1 seem to be protective. Only focusing on breast milk indicates that milk cytokines IL-5 and IL-13 have adverse effects. However, similar immune markers measured in maternal serum during late gestational period and in breast milk suggest that both maternal serum and breast milk whey may increase AS among infants. Regarding FAs, high levels of total n-6 PUFA in breast milk are associated with an increased risk for AS, whereas high levels of total n-3 PUFA decreased the risk of atopy. The findings suggest that the risk related to IL-5 and IL-13 and the protection due to whey IgA and TGF-beta-1 needs further research. In addition, effects of n-3 and n-6 PUFA on allergic disorders should be further explored. Cluster analyses combining individual risk markers should be applied in future studies to detect immune profiles associated with asthma-like symptoms.

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