An ADAM33 Polymorphism Associates with Progression of Preschool Wheeze into Childhood Asthma:A Prospective Case-Control Study with Replication in a Birth Cohort Study

The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined.To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma.In a prospective study, children with recurrent wheeze from the ADEM (Asthma DEtection and Monitoring) study were followed until the age of six. At that age a classification (transient wheeze or asthma) was based on symptoms, lung function and medication use. In 198 children the relationship between this classification and 30 polymorphisms in 16 asthma candidate genes was assessed by logistic regression. In case of an association based on a p<0.10, replication analysis was performed in an independent birth cohort study (KOALA study, n = 248 included for the present analysis).In the ADEM study, the minor alleles of ADAM33 rs511898 and rs528557 and the ORMDL3/GSDMB rs7216389 polymorphisms were negatively associated, whereas the minor alleles of IL4 rs2243250 and rs2070874 polymorphisms were positively associated with childhood asthma. When replicated in the KOALA study, ADAM33 rs528557 showed a negative association of the CG/GG-genotype with progression of recurrent wheeze into childhood asthma (0.50 (0.26-0.97) p = 0.04) and no association with preschool wheeze.Polymorphisms in ADAM33, ORMDL3/GSDMB and IL4 were associated with childhood asthma in a group of children with recurrent wheeze. The replication of the negative association of the CG/GG-genotype of rs528557 ADAM33 with childhood asthma in an independent birth cohort study confirms that a compromised ADAM33 gene may be implicated in the progression of wheeze into childhood asthma

Predictive value of serum sST2 in preschool wheezers for development of asthma with high FeNO

Wheezing is common in childhood. However, current prediction models of pediatric asthma have only modest accuracy. Novel biomarkers and definition of subphenotypes may improve asthma prediction. Interleukin-1-receptor-like-1 (IL1RL1 or ST2) is a well-replicated asthma gene and associates with eosinophilia. We investigated whether serum sST2 predicts asthma and asthma with elevated exhaled NO (FeNO), compared to the commonly used Asthma Prediction Index (API). Using logistic regression modeling, we found that serum sST2 levels in 2-3 years-old wheezers do not predict doctors' diagnosed asthma at age 6 years. Instead, sST2 predicts a subphenotype of asthma characterized by increased levels of FeNO, a marker for eosinophilic airway inflammation. Herein, sST2 improved the predictive value of the API (AUC=0.70, 95% CI 0.56-0.84), but had also significant predictive value on its own (AUC=0.65, 95% CI 0.52-0.79). Our study indicates that sST2 in preschool wheezers has predictive value for the development of eosinophilic airway inflammation in asthmatic children at school age

Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma

Background Mounting evidence suggests that fetal exposures may exert long-term effects on the function of the skin and of the immune system. This study aimed at assessing whether maternal complications during pregnancy are associated with an increased risk of eczema during childhood. Methods The associations between hypertension/preeclampsia, febrile infections, or gynecological infections during pregnancy and the occurrence of childhood eczema were studied in a population (n=3907) of children, aged 3-14yrs, living in Italy. Their parents filled in a standardized questionnaire about the presence of children's eczema and the events that occurred during pregnancy, birth, and the first year of the child's life. Results 7.7%, 3.8%, and 6.1% of the pregnancies were complicated by hypertension/preeclampsia, febrile infections, and gynecological infections, respectively. The prevalence of eczema was significantly higher in children born to mothers who had experienced febrile (35.5% vs. 22.0%;

d-PLS-DA score plot, projection of objects into the space of two PLS latent variables of data containing children with transient wheeze and asthma at the early age (inclusion age 2–4 years old).

<p>d-PLS-DA score plot, projection of objects into the space of two PLS latent variables of data containing children with transient wheeze and asthma at the early age (inclusion age 2–4 years old).</p

Flowchart of the different steps in data preprocessing and analysis.

<p>In step 7 model 1 corresponds to RF analysis of groups healthy and asthma, while model 2 to RF analysis of groups transient wheezers and asthma.</p

GC-<i>tof</i>-MS measurements and used parameters.

<p>GC-<i>tof</i>-MS measurements and used parameters.</p

Genetic variants associated with progression from preschool wheeze into childhood asthma in the ADEM study (n = 198) with replication in the KOALA Birth Cohort Study (n = 248)

<p>Genetic variants associated with progression from preschool wheeze into childhood asthma in the ADEM study (n = 198) with replication in the KOALA Birth Cohort Study (n = 248)</p

Projection into score 1, score 2 and score 3 delivered from PCA on proximities of RF model 2 (transient wheeze vs. asthma) and model 1 (healthy vs. asthma).

<p>(<b>A</b>) of all 1074 breath samples obtained from children collected over time starting at age 2 and finishing at age 6 years old; (<b>B</b>) of breath samples collected at early age (i.e. inclusion at age 2–4 years); (<b>C</b>) of breath samples obtained at day of final diagnosis (i.e. age 6 years old). Each breath sample is color-coded accordingly to group's membership: healthy, transient wheeze and asthma.</p

The outcomes of PCA and ROC analysis.

<p>(<b>A</b>) PCA score plot of 1074 breath-o-grams performed on 527 VOCs excreted in breath samples obtained from healthy, transient wheezing and asthmatic children. There is no clear grouping visible; (<b>B</b>) ROC curve for independent test set of the RF model obtained for groups healthy and asthma using 12 VOCs. The area under the curve is 85.8%; the sensitivity and specificity for the optimal cut-off of 0.52 (indicated as circle in the figure) are respectively equal to 81.5% and 74.2% (<b>C</b>) ROC curve for independent test set of the RF model obtained for groups transient wheezers and asthma using 12 VOCs. The area under the curve is 77.8%; the sensitivity and specificity for the optimal cut-off of 0.51 (indicated as circle in the figure) are respectively equal to 74.6% and 70%.</p