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Background IL13, IL4, IL4RA, FCER1B and ADRB2 are susceptible genes of asthma and atopy. Our previous study has found gene–gene interactions on asthma between these genes in Chinese Han children. Whether the interactions begin in fetal stage, and whether these genes interact with prenatal environment to enhance cord blood IgE (CBIgE) levels and then cause subsequent allergic diseases have yet to be determined. This study aimed to determine whether there are gene–gene and gene-environment interactions on CBIgE elevation among the aforementioned five genes and prenatal environmental factors in Chinese Han population. Methods 989 cord blood samples from a Chinese birth cohort were genotyped for nine single-nucleotide polymorphisms (SNPs) in the five genes, and measured for CBIgE levels. Prenatal environmental factors were collected using a questionnaire. Gene–gene and gene-environment interactions were analyzed with generalized multifactor dimensionality methods. Results A four-way gene–gene interaction model (IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713) was regarded as the optimal one for CBIgE elevation (testing balanced accuracy = 0.5805, P = 9.03 × 10–4). Among the four SNPs, only IL13 rs20541 was identified to have an independent effect on elevated CBIgE (odds ratio (OR) = 1.36, P = 3.57 × 10–3), while the other three had small but synergistic effects. Carriers of IL13 rs20541 TT, IL13 rs1800925 CT/TT, IL4 rs2243250 TT and ADRB2 rs1042713 AA were estimated to be at more than fourfold higher risk for CBIgE elevation (OR = 4.14, P = 2.69 × 10–2). Gene-environment interaction on elevated CBIgE was found between IL4 rs2243250 and maternal atopy (OR = 1.41, P = 2.65 × 10–2). Conclusions Gene–gene interaction between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and gene-environment interaction between IL4 rs2243250 and maternal atopy begin in prenatal stage to augment IgE production in Chinese Han children.

Background No reliable biological marker for the diagnosis of asthma in younger children is currently available. In this study, we analyzed the differences in basophil activation test (BAT) results among children with recurrent wheezing episodes who had different asthma outcomes. Results A prospective cohort study was conducted in children aged under 5 years who visited our pediatric respiratory clinic and ward for wheezing. After enrollment, the participants provided samples for a CD63-based BAT performed using an inhalant allergen mixture as a stimulant. Histories of personal allergic diseases and family allergic diseases were evaluated by using a questionnaire. All participants were followed up for 2 years, and their asthma outcomes were evaluated at the end of the follow-up period. The correlation between the BAT results and asthma outcomes was analyzed. Of the 45 originally enrolled children, 38 completed both the follow-up and a BAT. After stimulation with the inhalant mixture, the CD63 expression on basophils and the rate of positive CD63-based BAT results in children diagnosed with asthma were both significantly higher than those in children who were not diagnosed with asthma (p p Conclusions Our pilot study indicates that CD63-based BAT has potential clinical value for predicting asthma outcome in young children with wheezing episodes.

Background：Wheezing is an important respiratory symptom in the diagnosis of asthma. However, wheezing is common in children and often related to viral infection. This and the lack of reliable biological indicators for asthma create difficulty in diagnosing asthma early in children. Objective: In this study, the levels of CD4+CCR6+CRTh2+ memory Th2 cells in wheezing children with different diagnostic outcomes were investigated to determine correlation with a diagnosis of asthma and to assess their potential clinical value as a biological indicator for this disease. Methods: A prospective study was performed with a cohort of wheezing children aged 3 months to 6 years hospitalized in the Division of Pulmonary Pediatrics at Shanghai Xinhua hospital and Shanghai children’s medical center affiliated to Shanghai Jiao Tong University School of Medicine from July 2017 to March 2018. After inclusion, the level of serum IgE, presence of allergen-specific serum IgE (sIgE) and proportion of circulating CD4+CCR6+CRTh2+ memory Th2 cells were counted. In addition, the patients’ personal and family histories of allergic disease were acquired by questionnaire. The children were followed up annually over 2 years by telephone call with a guardian to record whether the child had been diagnosed with asthma. The accuracy of an increased proportion of CD4+CCR6+CRTh2+ memory Th2 cells as an indicator of asthma was assessed. Results: A total of 43 children completed follow-up. The median of circulating CD4+CCR6+CRTh2+ memory Th2 cells in wheezing children diagnosed with or without asthma was 1.2%(0.8%~2.9%) and 0.6%(0.1%~0.9%), respectively, and was significantly higher in children diagnosed with asthma (P 0.05). Conclusion: Our exploratory study found that an increase in the level of circulating CD4+CCR6+CRTh2+ memory Th2 cells could be used as a biological indicator for early diagnosis of asthma, especially in predicting the risk of asthma in atopic children.

Summary Rationale: IL13, IL4, IL4RA, FCER1B, and ADRB2 are important inflammatory genes associated with immunoglobulin E levels. This study attempts to determine whether there are gene–gene interactions in the five genes among asthmatic children of Chinese Han nationality. Methods: Nine single-nucleotide polymorphisms (SNPs) in the five genes were genotyped in 1,000 asthmatic children and 1,000 healthy controls using TaqMan real-time quantitative polymerase chain reaction. Multifactor–dimensionality reduction method was applied for the analysis. Results: A four-way gene–gene interaction model consisting of IL13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108 was chosen as the optimal one for determining asthma susceptibility (testing balanced accuracy = 0.6089, cross-validation consistency = 10/10, P = 6.98E−05). Each of the four SNPs was identified to have an independent association with childhood asthma (G allele of rs20541, odds ratio (OR) = 1.24, P = 1.23E−03; T allele of rs2243250, OR = 1.25, P = 3.81E-03; A allele of rs1042713, OR = 1.29, P = 6.75E-05; G allele of rs569108, OR = 1.27, P = 3.86E−03). Individuals homozygous for the risk alleles at all the four loci (rs20541 GG, rs2243250 TT, rs1042713 AA, and rs569108 GG) had a significantly higher risk of asthma compared with those without any risk homozygotes (OR = 13.55, P = 4.28E−03), and also greater than those with less than four risk homozygotes (OR = 10.09, P = 6.51E−03). Conclusions: Our results suggest that IL13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108, four SNPs with significant sole effect on asthma, interact to confer a higher risk for the disease in Chinese Han children. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc.

Background: IL-13 (interleukin-13) and RANTES (Regulated upon Activation, Normal T cells Expressed and Secreted) are the important asthma inflammatory mediators. Objective: The present study aimed to investigate the single and combined associations between the polymorphism (SNP) loci in IL-13 and RANTES genes with the development of asthma in children of Chinese Han nationality. Methods: The risk associated with genotypes of three IL-13 SNPs and two RANTES SNPs was determined by the χ 2 test in 384 children with asthma and an equal number of healthy controls matched by sex. Results: Between the experimental and control groups, no statistically significant differences ( P >0.05) were found in genotype distribution and allele frequency among three loci (IL-13 C-1112T, IL-13 C1923T, and RANTES A-403G ). However, significant diversity was observed among IL-13 A2044G ( P =0.0001) and RANTES G-28C ( P =0.0001). Moreover, the frequency of IL-13 A2044G A/A and RANTES G-28C G/G in the asthma group was significantly higher than in the control group (odds ratio [OR] =2.59, P =0.0001; OR =3.00, P =0.0001, respectively). Carriers of both IL-13 A2044G A/A and RANTES G-28C G/G have a more significant risk for developing asthma than those with only a single polymorphism. Conclusions: The three loci ( IL-13 C-1112T, IL-13 C1923T, and RANTES A-403G ) make little contribution to the development of asthma in children of Chinese Han nationality. IL-13 A2044G and RANTES G-28C are significantly associated with childhood asthma. IL-13 A2044G A/A and RANTES G-28C G/G have a significant and combined effect on the development of asthma.

PURPOSE Interleukin (IL)-13, a Th2-type cytokine, plays a pivotal role in the pathogenesis of asthma through its direct effects on airway smooth muscles. A naturally occurring IL-13 polymorphism, R110Q, is strongly associated with increased total serum IgE levels and asthma. In the present study, we aimed to determine whether the IL-13 R110Q variant would display different biochemical properties or altered functions in comparison with wild-type (WT) IL-13 in cultured human bronchial smooth muscle cells (hBSMCs). METHODS Culture supernatants and cell proteins were collected from cultured hBSMCs that were treated with 50 ng/mL IL-13 or IL-13 R110Q for 24 hours. Eotaxin released into hBSMC culture medium was determined by ELISA. The expression levels of the high-affinity IgE receptor (FceRI) α-chain, smooth muscle-specific actin alpha chain (α-SMA), smooth muscle myosin heavy chain (SmMHC), and calreticulin in the cells were measured on Western blots. RESULTS Compared with WT IL-13, treatment with the IL-13 R110Q variant resulted in a significant increase in eotaxin release as well as significant, although modest, increases in the expression levels of α-SMA, SmMHC, calreticulin, and FceRI α-chain. CONCLUSIONS The results of the present study suggenst that the IL-13 R110Q variant may enhance enhanced functional activities in hBSMCs.

Background and Aim: Multidrug resistance (MDR) compromises the efficacy of chemotherapy. Many approaches have been used to reduce MDR; however, the results are poor. It has been reported that iron deprivation downregulates MDR genes. To investigate the relationship of iron with MDR and early growth response gene-1 (EGR1), we investigated the effect of iron deprivation on expression and/or function of multidrug resistance-1 (MDR1), early growth response gene-1 (EGR1), ferritin heavy chain gene (H-Fn) and MDR1-encoded P-glycoprotein (P-gp) in the K562 leukemic cell line. Methods: The cells were stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and incubated with either FeCl3 or the iron-chelating drug DFO. The mRNA levels of MDR1, EGR1 and H-Fn were detected by RT-PCR. The protein expression and function of P-gp were measured by immunohistochemical staining and flow cytometry, respectively. Results: DFO significantly reduced the intracellular iron level, and led to ∼70% reduction of MDR1 mRNA, ∼50% of reduction of H-Fn mRNA and ∼30% reduction of P-gp protein in TPA-differentiated K562 cells. The P-gp pump function, measured by daunorubicin exclusion, was also reduced by DFO treatment. Conclusions: These results suggest a close relationship between iron deprivation and reduced MDR1/P-gp expression and function. DFO may be used together with chemotherapeutic drugs to achieve better clinical efficacy.