Association Of New Identified Susceptibility Loci And Atopic Dermatitis In The Chinese Han Population

Background Atopic dermatitis(AD)is a common,chronic recurrent and inflammatory skin disease with a complicated pathogenesis including genetic and environmental factors.It has a continuously increasing incidence among people in recent decades and now affects up to over 17% of children in the developed world.The genetic components have been demonstrated to play crucial roles in the development of AD.Recent large-scale genome-wide association studies(GWASs)of atopic dermatitis were performed in European,Chinese,Japanese,and Korean populations.More than 30 susceptibility loci at genome-wide significance were identified,mostly implicated in epidermal barrier abnormalities and immune dysregulation.In 2012,we performed a GWAS of AD in a Chinese Han population,and identified two new susceptibility loci at5q22.1 and 20q13.33.In 2015,the EArly Genetics and Lifecourse Epidemiology(EAGLE)Consortium conducted an international collaborative project in search of AD susceptibility loci,in which dozens of research groups from several countries participated.The project carried out a multi-ancestry meta-analysis of 26 individual studies comprising 21,399 cases and 95,464 controls and identified 27 susceptibility loci including of 11 new ones associated with AD.Most of these loci are implicated in immunoregulation,stressing the crucial contribution of immune mechanisms to atopic dermatitis pathogenesisObjectives To investigate whether these 11 new susceptibility loci is associated with AD in Chinese Han population,and search new susceptibility gene for AD.Methods We obtained the genotype data of these 11 loci in adjacent upstream/downstream 250 kb regions from the GWAS dataset in Chinese Han populations.Genotype imputation was done for each SNP with IMPUTE v2.2.2.We extracted the information of the same SNPs or SNPs showing strong linkage disequilibrium(LD)with index SNPs(r2 ? 0.8)in the 11 loci based on previous GWAS database and genotype imputation data.SNPs were filtered based on the following quality criteria: 1)the P value was < 0.05;2)P-value for Hardy–Weinberg equilibrium(PHWE)in controls > 0.0001;3)minor allele frequency(MAF)?1% both in cases and controls.The selected SNPs with suggestive signals were genotyped in a large-scale replication study with a total of 4619 cases and 10,789 controls using the Sequenom Massarray system.Association analyses were performed using PLINK 1.07 software.Results were combined across our previous AD-GWAS stage and the replication stage by meta-analysis.Bioinformatic analysis was done to predict the possible causal gene.Results Of the 11 SNPs investigated,four SNPs passing quality control were included for further validation.Of the four selected SNPs,three were further genotyped in 4,619 AD cases and 10,789 healthy controls,while one(rs2038255)failed in the assay design by Sequenom.SNP rs112111458 showed significant association in the independent replication populations(P = 7.37 × 10-7,OR = 0.86).When the genotypic data from our previous GWAS and the replication study were combined using meta-analysis under a fixed-effects model,one suggestive association was discovered at rs112111458(Pmeta =8.18 × 10-08,OR = 0.69).The SNP rs112111458 is located at chr2p13.3 and 37 kp upstream of CD207.Further functional annotation by Haplo Reg indicated that transcriptional regulation activity exists at this locus for the CD207 gene in skin tissue.Conclusions Our study confirmed a previously reported susceptibility loci in the Chinese Han population,which implicates CD207 might be a new susceptibility gene for AD and highlights the crucial role of immune responses in AD.