Optimization And Validation Of The Predisposing Gene Model For Predicting Childhood Asthma In Han Nationality

Part I Optimization of the predisposing gene model for predicting childhood asthma in Han nationality Objective: To optimize the predisposing gene model for predicting childhood asthma in Han nationality in a larger sample,which has been established before and consisted of IL13-1112C>T,IL13 +1923C>T,IL13 R110 Q,IL4-590C>T,ADRB2 R16 G,FCER1B-109C>T,FCER1 B E237G,IL4 RA I75V and IL4 RA Q551R.Methods: The aforementioned nine single-nucleotide polymorphisms(SNPs)in the five genes were genotyped in 1000 asthmatic children and 1000 healthy controls.Multifactor-dimensionality reduction method was applied to detect gene-gene interactions among those SNPs.Results: A four-way gene-gene interaction model consisting of IL13 R110 Q,IL4-590C>T,ADRB2 R16 G and FCER1 B E237G 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 IL13 R110 Q,OR = 1.24,P = 1.23E-03;T allele of IL4-590C>T,OR = 1.25,P = 3.81E-03;A allele of ADRB2 R16 G,OR = 1.29,P= 6.75E-05;G allele of FCER1 B E237G,OR = 1.27,P = 3.86E-03).Individuals homozygous for the risk alleles at all the four loci(IL13 R110 Q GG,IL4-590C>T TT,ADRB2 R16 G AA and FCER1 B E237G 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).Conclusion: Our results suggest that IL13 R110 Q,IL4-590C>T,ADRB2R16 G and FCER1 B E237G constitute the optimized predisposing gene model for predicting childhood asthma in Han nationality.Each of the four SNPs has an independent effect on the development of asthma,and the combined effects are significantly stronger.Part II Validation of the optimized predisposing gene model for predicting childhood asthma in Han nationality: a birth cohort study Objective: To validate the optimized predisposing gene model for predicting childhood asthma in a birth cohort,which consists of IL13 R110 Q,IL4-590C>T,ADRB2 R16 G and FCER1 B E237G.Methods: The aforementioned four SNPs were genotyped in 711 newborns from a birth cohort using matrix-assisted laser desorption / ionization time of flight mass spectrometry.According to the optimized predisposing gene model for predicting childhood asthma in Han nationality,all the children were divided into two groups,asthma high-risk group and low-risk group.ImmunoCAP Total Low Range Assay was applied to measure cord serum IgE(CS-IgE)concentration.The children were followed up until two years oldand the follow-up questionnaire and interview provided information about allergic diseases.CS-IgE level and the prevalence of allergic diseases were compared between asthma high-risk and low-risk groups.Results: There were 334 children in asthma high-risk group and 377 in low-risk group.31.08% of the asthma high-risk children had an increased CS-IgE level,which was significantly higher than 24.33% of the low-risk children(OR(95%CI)=1.40(1.01-1.96),P=4.63E-02).The prevalence of eczema in asthma high-risk group was significantly greater than that in low-risk group(32.28% and 24.60%,respectively.RR(95%CI)=1.31(1.02-1.70),P=3.72E-02),while no differences were found between the two groups in the prevalence of food allergy,wheezing and rhinitis(P>0.05).In asthma high-risk group,43.51% of the children had aforementioned allergic diseases or symptoms,which was significantly higher than 35.14% of the low-risk children(RR(95%CI)=1.24(1.01-1.51),P=3.63E-02).Conclusion: CS-IgE levels and prevalence of allergic diseases in asthma high-risk group are greater than those in low-risk group.The birth cohort need a long-term follow-up,so that it can be determined whether the optimized predisposing gene model is useful in predicting childhood asthma in Han nationality.Part ? Validation of the predisposing gene model for predicting childhood asthma in wheezing children Objective: To validate the optimized predisposing gene model for predicting childhood asthma in wheezing children,which consists of IL13 R110 Q,IL4-590C>T,ADRB2 R16 G and FCER1 B E237G.Methods: TaqMan real-time quantitative polymerase chain reaction was applied to genotype the aforementioned four SNPs in 212 wheezing children.All of these children were divided into two groups,asthma high-risk and low-risk groups,according to the optimized predisposing gene model for predicting childhood asthma in Han nationality.Loose and stringent asthma prediction indices(API)were used to classify the wheezing children respectively.Percentage of children with a positive loose or stringent API was compared between asthma high-risk group and low-risk group.Results: There were 95 children in asthma high-risk group and 117 in low-risk group.No difference existed in sex and age between the two groups.85(89.47%)of the asthma high-risk children had a positive loose API,which was significantly more than 61(52.14%)of the low-risk children(OR(95%CI)= 7.80(3.69-16.50),P = 5.26E-09).In asthma high-risk group,71(74.74%)children had a positive stringent API,which was also significantly more than 21(17.95%)in the low-risk group(OR(95%CI)= 13.52(6.98-26.20),P=1.07E-16).Conclusion: asthma high-risk children more often had a positive loose or stringent API than did those with low risk.There is a strong link between the gene model and API.Long-term follow-up of the wheezing children is necessary to determine whether the optimized predisposing gene model is a useful tool for predicting childhood asthma in Han nationality.