| Background:Atopic diseases, including atopic dermatitis (AD), allergic rhinitis (AR)and asthma (AS), belong to the hereditary and hypersensitivity diseases and theircommon features have strong familial tendency, positive skin test items, and high levelsfor total serum and specific IgE. In developed countries, the overall incidence of atopicdiseases is about20%. Epidemiological studies have shown that the developmentprocess of atopic diseases is generally AD pathogenesis in infancy, followed bycomitant with the incidence of AR and/or AS in children. Studies have shown that theheritability of AD, AR, AS were0.71-0.84,0.33-0.91,0.35-0.95. Over the years,scholars have searched susceptibility genes for atopic diseases by applying a variety ofresearch strategies, such as, the genome-wide linkage analysis study, the candidate genestudy and the genome-wide association study (GWAS), and have successfully achievedsome progress. Genetic studies of atopic diseases are extremely complex due to geneticindividual differences, the gene-gene interactions and the gene-environment interactions.Therefore, a single gene variant can not fully explain the development of atopic diseases,but should understand the interactions of genetic variants, including gene-gene andgene-environment interactions on genetic effects, which are essential to the study foratopic diseases.The completion of the Human Genome Project (HGP) and the Human GenomeHaplotype Mapping Project (HapMap) facilitated the rapid development ofhigh-throughput gene genotyping technologies and the reduction of genotyping costs,which made genome-wide association study become reality in large-scale approaches.The method of genome wide SNPs analysis is highly effective to uncover disease susceptibility genes. GWAS is one of the most effective ways currently described toidentify susceptibility genes of complex diseases. The success of a large number ofGWAS shows a strong efficiency to uncover susceptibility genes for complex diseases,which provide new ideas and methods to search susceptibility genes for atopic diseases.Currently, more than35susceptibility genes/loci have been found for atopic diseasesby using GWAS. In European and Chinese Han populations, several susceptibility genesor loci were identified by GWAS of AD, such as1q21.3(FLG),5q22.1(TMEM232/SLC25A46),11q13.5(C11orf30), and20q13.33(TNFRSF6B/ZGPAT).Molecular genetics studies have shown that atopic diseases might share commonsusceptibility genes as to having same clinical features and a significant familialaggregation tendency for AD, AR and AS, or different genotypes might appear thedifferent phenotypes of atopy. There may be a specific gene for a phenotype of atopy, orwhich may be caused by gene-gene interactions. In view of this, AD, AR and AS mayshare a common genetic predisposing factors.Objective: To investigate the common susceptibility genes/loci in atopic diseases byidentifing susceptibility genes/loci of AR and AS (from the associated genes/loci forGWAS of AD in Chinese Han population) and analyzing the gene-gene interactions tothe effect of pathogenesis.Methods:(1) SNPs selection: In our previous GWAS of AD, we identified sevenassociated SNPs (1q21.3, FLG, rs11204971and rs3126085;5q22.1,TMEM232/SLC25A46, rs10067777, rs7701890, rs13360927and rs13361382;20q13.33,TNFRSF6B/ZGPAT, rs6010620) in Chinese Han population; The11q13.5(C11orf30)was identified for AD susceptibility locus in European population, therefore, weselected2SNPs rs7936562(P=1.81×10-2) and rs7124842(P=1.49×10-2) with the most significant P value in this locus according to our AD-GWAS data; In addition, thegenome-wide linkage analysis showed that14q11.2was a susceptibility locus for AS inthree different races, and we inferred that this locus may implicate some susceptibilitygenes for atopic diseases, so we select a SNP rs4982958(P=4.42×10-3,CMA1) withthe most significant P value in this locus according to our AD-GWAS data. A total of10SNPs were genotyped in AR, AS cases and controls samples. The genotyping data for10SNPs in4636AD cases and13559controls derived from our previous GWAS ofAD.(2) Replications: The above selected10SNPs were genotyped in363AR cases and668cases,463AS cases and985controls by Sequenom MassArray system. After dataprocessing and quality control, the genotye data were analyzed by genetic statistics.(3) Interaction analysis: The4SNPs (rs10067777, rs7701890, rs13360927andrs13361382) at5q22.1and2SNPs (rs3126085and rs11204971) at1q21.3(FLG)represent an association signal, respectively. Therefore, we selected SNPs rs13360927and rs3126085for interaction studies. In addition, a suggestive locus10q21.2(rs2393903, ZNF365) was identified by our previous AD-GWAS. A total of7SNPs(1q21.3, FLG, rs3126085;5q22.1, TMEM232/SLC25A46, rs13360927;10q21.2,ZNF365, rs2393903;11q13.5, C11orf30, rs7936562and rs7124842;14q11.2, CMA1,rs4982958;20q13.33, TNFRSF6B/ZGPAT, rs6010620) were selected for interactionstudies in4636AD cases and13559controls,1473AD with AR cases and13559controls,2993AD without AR cases and13559controls,621AD with AS cases and13559controls,3846AD without AS cases and13559controls. The above allgenotyping data derived from our previous AD-GWAS; In the analysis of the AR andAS, a total of6SNPs (1q21.3, FLG, rs3126085;5q22.1, TMEM232/SLC25A46, rs13360927;11q13.5, C11orf30, rs7936562and rs7124842;14q11.2, CMA1, rs4982958;20q13.33, TNFRSF6B/ZGPAT, rs6010620) were selected for interaction studies in363AR cases and668controls,463AS cases and985controls.(4) Biological network analysis for genes: Based on biological function, the8genes(FLG, TMEM232, SLC25A46, ZNF365, C11orf30, CMA1, TNFRSF6B and ZGPAT)from5loci were investigated for biological network analysis by By Ingenuity PathwayAnalysis (IPA) system.Results:(1) The results of SNPs analysis in AD: Seven SNPs (FLG: rs11204971,rs3126085;5q22.1: rs7701890, rs10067777, rs13360927, rs13361382;20q13.33:rs6010620) were associated with AD susceptibility (P <5.00×10-8); Two SNPs(rs7936562and rs7124842) at11q13.5(C11orf30) were weak associated with ADsusceptibility (P=2.98×10-4, P=8.49×10-3). Haplotype association analysis, the riskhaplotype GA from2SNPs (rs11204971and rs3126085) at1q21.3(FLG) wasassociated with AD susceptibility (P=7.62×10-10), the risk haplotype GGGA from4SNPs (rs10067777, rs7701890, rs13360927and rs13361382) at5q22.1(TMEM232/SLC25A46) was associated with AD susceptibility (P=1.20×10-10), therisk haplotype CG from2SNPs (rs7936562and rs7124842) at11q13.5(C11orf30) wasassociated with AD susceptibility (P=3.30×10-6). In interacton analysis, theinteraction between rs13360927within5q22.1and rs2393903within ZNF365withcarrying the minor allele G was significant in AD with AR cases and controls (P=0.02),the interaction between rs13360927genotype G/A+G/G and rs2393903genotype G/Gwas also significant in AD with AR cases and controls (P=0.008).(2) The results of SNPs analysis in AR: The risk allele C for SNP rs4982958at14q11.2 (CMA1) was associated with AR susceptibility (P=0.002); For rs4982958, the mostsignificant association evidence was observed under recessive model by genetic modelanalysis (P=8.00×10-4). In clinical phenotype stratified analysis, the risk allele C wasassociated with clinical classification (persistent AR)(P=9.00×10-5) and positivenumber of SPT (>2)(P=3.00×10-4), the frequency of risk allele C was significanthigher in patients with persistent AR than those patients with intermittent AR (74.2%vs65.4%, P=0.01), the frequency of risk allele C was also significant higher in patientswith the positive number of SPT>2than those patients with the positive number ofSPT≤2(71.7%vs63.3%, P=0.038). The risk allele G for SNP rs6010620at20q13.33(TNFRSF6B/ZGPAT) was associated with clinical classification (persistent AR)(P=0.006), the frequency of risk allele G was significant higher in patients with persisitentAR than those patients with intermittent AR (32.6%vs24.7%, P=0.019); Haplotypeassociation analysis showed that the2SNPs (rs7936562and rs7124842) at11q13.5(C11orf30) constituting the risk haplotype CG was associated with AR susceptibility (P=0.007).(3) The results of SNPs analysis in AS: The risk allele C for SNP rs4982958at14q11.2(CMA1) was associated with AS susceptibility (P=3.04×10-4); For rs4982958, themost significant association evidence was observed under recessive model by geneticmodel analysis (P=3.00×10-4). Haplotype association analysis showed that the4SNPs (rs10067777, rs7701890, rs13360927and rs13361382) at5q22.1(TMEM232/SLC25A46) constituting the risk haplotype GGGA was associated with ASsusceptibility (P=0.01).(4) The result of biological network analysis for genes: By IPA system, a significantnetwork (a significant score21) of7genes of8was identified through unsupervised network analysis (FLG, SLC25A46, ZNF365, C11orf30, CMA1, TNFRSF6B andZGPAT).Conclusion: In this study, we replicated the associated genes/loci from GWAS of ADin AR and AS cases by association analysis. In AR and AS cases, the study identified anew susceptibility locus and validated a susceptibility locus14q11.2(CMA1). In ADand AS cases, the study identified a risk haplotype at5q22.1(TMEM232/SLC25A46)that was associated with AD and AS. The locus20q13.33(TNFRSF6B/ZGPAT) wasassociated with persistent AR susceptibility in cases, which suggested a commonsusceptibility locus for AD and AR. A significant risk haplotype in11q13.5(C11orf30)was also identified in AD and AR cases. The interaction between5q22.1(TMEM232/SLC25A46) and ZNF365was significant in AD patients concomitant withAR, the combined effect for the genetic variants within them may affect AD withconcomitant atopic phenotypes AR based on the analysis of biological networks. Thisstudy not only advanced the understanding on the genetic basis of atopic diseases, butalso was very significant to reveal the common genetic pathogenesis of atopic diseases. |
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