Validation And Application Of The Gene Model For Predicting Asthma Susceptibility In Han Children

Part 1 Validation of the gene model for predicting asthma susceptibility of Han children in preschool wheezing childrenObjective To validate the previously established gene model for predicting asthma susceptibility of Han children in preschool wheezing children,which consisted of ADRB2 rs1042713,IL4 rs2243250,FCER1 B rs569108 and L13 rs20541.Methods Four single nucleotide polymorphisms in the genes were genotyped in 385 preschool wheezing children by the method of matrix-assisted laser desorption ionization time-of-flight mass spectrometry.The high risk and low risk genotypes for asthma were evaluated acco rding to different genotypes carried by each patient.Serum specific Ig E was tested by Immuno CAP method.Associations between the gene model and asthma predictive index and atopy were analyzed.Results The percentage of patients with the positive loose asthma predictive index was signifcantly higher in the high risk genotype group tha n that in the low risk group(68.4% vs.47.9%,P=5.12E-5,OR(95%CI)=2.36(1.55-3.58)).Compared with the low risk genotype group(22.7%),more children were positive for stringent asthma predictive index in the high risk genotype group(54.6%)and the difference was statistically significant(P=1.22E-10,OR(95%CI)=4.08(2.63-6.33)).More atopic patients were found in the high risk genotype group than those in the low risk group(71.8%vs.55%,P=0.006,OR(95%CI)=2.09(1.22-3.55)).Conclusion The asthma susceptibility genes prediction model of Han children was associated with asthma predictive index and atopy,which provide evidence for determining high risks of developing asthma and atopy in Chinese Han children.Part 2 Validation the gene model for predicting asthma susceptibility of Han children in 5 year old children: a birth cohort studyObjective To validate the four locus gene model consisting of ADRB2 rs1042713,IL4 rs2243250,FCER1 B rs569108 and L13 rs20541 in a birth cohort of 5-year old children.Methods The four single nucleotide polymorphisms were genotyped in 309 children in the birth cohort.The high and low risk genotypes for asthma were defined according to the four locus gene model.Allergens were tested by the method of skin prick test.The follow up questionnaire showed information about their allergic diseases at 5-year old.Differences about allergic diseases and the results of skin prick test in the two risk groups for asthma were analyzed.Results The prevanlence of allergic rhinitis in high and low risk genotype groups were 58.95% and 41.05% respectively,and the difference was statically significant(P=0.04,RR=1.69).61.29% of children had wheezing symptom in high risk group,which was significantly higher than 38.71% of low risk group(P=0.01,RR=1.91).More children with high risk genotypes were positive in at least one allergic disease than those with low risk genotypes(55.61% vs.44.39%,P=0.02,RR=1.74).There were statistically significant differences between the two groups in terms of wheezing symptoms(P=0.02,RR=1.83)and at least one allergic disease(P=0.03,RR=1.72)after adjusting confounding factors.No differences were existed between the two groups in the prevalence of eczema,asthma and cough variant asthma(P(29)0.05).The number of animal dander especially cat dander sensitization were significantly higher in high risk group than that in low risk group(animal dander: 65.91%vs.34.09%,P=0.02,RR=2.26;cat dander: 73.08%vs.26.92%,P=0.015,RR=3.07),and the statistical differences were found after adjusting confounding factors(animal dander:P=0.026,RR=2.21;cat dander: P=0.018,RR=3.06).Besides,more children in high risk group were sensitive to more than 2 kinds of a llergens(P=0.011,RR=2.59;adjusted P=0.029,RR=2.34)regardless of the confounding factors.Conclusions More children in high risk group have higher prevanlence of wheezing symptoms and at least one allergic disease and were sensitive to more than 2 kinds of allergens than those in low risk group,indicating that the gene model can predict the occurrence of al ergic diseases in a certain degree.Part 3 Influence of the gene model for predicting asthma susceptibility on the outcomes of asthmaObjective To explore the influence of a four locus gene model consisting of ADRB2 rs1042713,IL4 rs2243250,FCER1 B rs569108 and L13 rs20541 on the outcomes of asthma.Methods Four single nucleotide polymorphisms were genotyped in 139 patients with different asthma outcomes(clinical remission,replase or persistence).The high risk and low risk genotypes for asthma were evaluated according to different genotypes that they carried.Differences about asthma outcomes in the two risk genotype groups and the factors affecting asthma prognosis were analyzed.Results More patients with high risk genotypes had severe asthma attacks than those with low risk genotypes(56.45%vs.40.23%,P=0.027).Compared with those with asthma clinical remission,patients with severe asthma attacks were risk factors for asthma relapse(P=0.021,OR= 3.19)and asthma presistence(P=0.024,OR=2.95),and smoking was a risk factor for asthma persistence(P=0.029,OR=3.27).The older age of asthma onset,the more likely it was persistent(P=0.001,O R=1.07),but it has no effect on asthma replase.There were no differences about outcomes of asthma in the two risk genotype groups(P(29)0.05).The age of asthma onset was younger than 6 year-old(P=0.037,O R=2.06;adjusted P=0.047,OR=2.05)and the course of asthma was longer than 4 years(P=0.033,OR= 2.28;adjusted P=0.045,OR=2.22)in the high risk group than those in the low risk group regardless of the confounding factors.Conclusions Patients with high risk genotypes had more severe asthma attacks and younger age of asthma onset and longer course,which suggested that the gene model was correlated with patients' condition and the age of asthma onset and asthma course.The age of asthma onset and severity as well as smoking were risk factors for asthma outcomes.Part 4 Application of the gene model for predicting asthma susceptibility in minorityObjective To study whether the four locus gene model consisting of ADRB2 rs1042713,IL4 rs2243250,FCER1 B rs569108 and L13 rs20541 was applicable to the Kazak children in Xinjiang.Methods Four single nucleotide polymorphisms about the 4 genes were genotyped in asthma group and control group of Han nationality and Kazak nationality respectively.The frequencies of different genotypes and alleles were compared between the asthma group and the normal group in the two nationalities.Different risk genotypes for asthma were evaluated in the two nationalities.Results The differences about frequencies of genotypes in ADRB2 rs1042713 and IL4 rs2243250 and IL13 rs20541 between asthma group and control group were statistically significant in Han children(ADRB2 rs1042713: P=0.004;IL4 rs2243250: P=0.008;IL13 rs20541: P=0.001),as were the frequencies of alleles in the aforementioned 3 single nucleotide polymorphisms(ADRB2 rs1042713: P=0.038;IL4 rs2243250: P=0.019;IL13 rs20541: P=0.007),but there were no statistical differences in FCER1 B rs569108(P(29)0.05).For the Kazak children,no differences were existed among all the genotypes and alleles in asthma group and control group.For the Han children,more children had asthma high risk genotypes in asthma group than those in control group(45.54% vs.23.91%,P=0.003,OR(95%CI)= 2.66(1.43-4.94)),and no difference was found in Kazak children.Conclusion The four locus gene model was applicable to Han children but not for the Kazak children in Xinjiang,which illustrating that the difference of asthma prevalence between different races is closely related to the genetic background.