Association Of 5q22.1 Region And Atopic Dermatitis In The Chinese Han Population

Background Atopic dermatitis(AD) is a chronic inflammatory skin disease that is characterised by intense itching and recurrent eczematous lesions. Although the aetiology of AD remains unclear, there is many evidences for AD as a polygenic disease caused by genetic and environmental factors. In 2011, we performed a genome-wide association study(GWAS) of AD in a Chinese Han population using 1,012 AD patients and 1,362 controls, and found that the 5q22.1 region was significantly correlated with AD. The transmembrane protein 232(TMEM232)/solute carrier family 25 member 46(SLC25A46) were thought to be candidate genes by interval gene function analysis and bioinformatics prediction.Objectives In order to define the causal gene at 5q22.1 for AD. To investigate the genetic model and genotype- phenotype correlation of causal gene, conducte susceptibility gene function studies.Methods The imputation analyses at 5q22.1 region were done based on the previous GWAS data, and the suggestive insertion/deletion(indel) and single nucleotide polymorphism(SNP) variants were genotyped in a large Han population by Sequenom Mass Array system. Immunohistochemistry(IHC) was performed to observe the expression of the gene.Results The topic of genetic research phase included 3013 AD cases and 5075 healthycontrol samples. Immunohistochemical study included 5 AD cases and 10 healthy control samples. Sample of AD are diagnosed by Hanifin and Rajka criteria. In order to define AD susceptibility gene of 5q22.1 region, the imputation were done using the previous GWAS database, which found 3,382 SNPs and 188 insertion/ deletion(insert/ deletion, indel) including of 15 indel variants with P<0.01. We selected ten indels(P<0.01 and MAF>0.05) and the four significant SNPs(rs10067777, rs7701890, rs13360927 and rs13361382) in 5q22.1 region from GWAS for genotyping in 3,013 AD cases and 5,075 controls by the Sequenom Mass Array system. Three indels were significant associated with AD. The rs11357450 was identified as a strongest related signal for AD by stepwise logistic regression analysis.The genetic model analysis revealed the homozygous /heterozygous odds ratio with deletion(D)/insert(I) genotype of rs11357450. ID heterozygotes increased AD risk(P = 4.01E-03, OR = 1.20, 95% CI = 1.06-1.36); dominant model provided a best fit for the association with AD(P = 1.96E-03, OR = 1.22; 95% CI = 1.07-1.37). Stratified analysis showed that allele D had significant statistically significant with southern regional group(P = 6.63E-06, OR = 1.34,95% CI = 1.18-1.53), and negative AD family history(P = 2.08E-17, OR = 0.48,95% CI = 0.40-0.57).By means of bioinformatic analysis, the deletion rs11357450 located at intron of TMEM232 gene,coincided with H3K4Me1 histone modification signals, as well as change of transcription factor binding sites. Immunohistology experiment was used to clarify the expression of the gene in AD lesions. TMEM232 positive cells were observed in epidermis, sebaceous glands and sweat glands of all samples. The expression intensity of TMEM232 increased gradually from the granular layer to the basal layer in normal tissures and reversed from the AD lesions. Meanwhile, the positive cytoplasm staining was found in lymphocytes around blood vessels in AD patients.Conclusions The study has identified TMEM232 as susceptibility gene of AD, and provided a new evidence to increase our understanding of the biological pathways in AD.