Association Study On Vitiligo Susceptible Gene Of Caucasians In The Chinese Han Population

Background Vitiligo is a common autoimmune skin disease in which the loss function of melanocyte results in the pigmentation of the skin or mucosa.Global epidemiological surveys have shown that the incidence is 0.2%-1.8%,while the incidence of vitiligo is about 0.56%in Chinese population.Its underlying pathobiology is still unclear,which involves melanocyte self-destruction theory,genetic theory,neurology theory,autoimmune theory,and oxidative stress theory.In recent years,genome-wide association study（GWAS）has been widely used to find susceptible genes for complex diseases.Since 2010,the Spritz group has performed several large-scale vitiligo GWASs in European populations and found 49 susceptible genes/loci associated with vitiligo.To date,some of these reported susceptibility genes have not yet been validated in the Chinese Han population.Objectives To investigate whether there is associations between vitiligo susceptibility genes of European population and Chinese Han population,and search for new susceptibility genes of vitiligo in Chinese Han population.Methods A total of 2581 cases of vitiligo and 2579 normal controls were collected.First,we obtained 16 genes/loci after excluding those which have been validated.Second,we obtained the genotype data of these 16 genes/loci from the vitiligo GWAS dataset in Chinese Han populations.Genotype imputation was done by IMPUTE v2.2.2.The 16 most significant SNPs were screened according to the following quality criteria:（1）the P-value was<10^-3;（2）call rates>90%;（3）minor allele frequency（MAF）>0.05 in controls;（4）P-value for Hardy-Weinberg equilibrium(P_HWE)>0.01 in controls.The 16 top SNPs with suggestive signals together with the reported SNPs were genotyped in a replication study with a total of 2581 cases and2579 controls by the Sequenom platform.PLINK 2.0 software was used to perform association analyses.Db SNP,Haplo Reg and e QTL were used to annotate the biological function to predict the possible causal gene.Results Of the 32 SNPs investigated,six SNPs failed in primers design,and a total of26 SNPs in 16 loci were genotyped in 2581 vitiligo patients and 2579 controls.The four SNPs were significantly associated with vitiligo in Chinese Han population,including of rs3747517(OR:0.87,95%CI:0.80-0.95,P=1.29×10^-3)at 2q24.2,rs4822024(OR:0.67,95%CI:0.58-0.76,P=6.37×10^-10)at 22q13.2,rs4807000(OR:0.66,95%CI:0.61-0.71,P=7.78×10^-24)and rs6510827(OR:1.19,95%CI:1.09-1.29,P=3.65×10^-5)at19p13.3.In the stratification analyses of clinical phenotypes,22q13.2（rs4822024）was significantly associated with segmental vitiligo patients(P=1.76×10^-5).In addition,19p13.3（rs4807000,rs6510827）and 22q13.2（rs4822024）had significant association with non-segmental vitiligo patients(P=2.49×10^-16;P=1.66×10^-4;P=4.87×10^-8,respectively).No statistically significant difference in the genotypic distribution between segmental vitiligo patients and non-segmental vitiligo patients.Accoding to db SNP database,rs3747517 is a missense variant of IFIH1 located in the 2q24.2 region,rs4807000 and rs6510827 are located in TICAM1 in the 19p13.3 region,and rs4822024is located 6kb upstream of the TEF in the 22q13.2 region.Further using Haplo Reg and e QTL for biological function prediction,it is found that rs4807000,rs6510827 and rs4822024 are involved in regulating gene expression.Conclusions Our study confirmed that 2q24.2（rs3747517）,19p13.3（rs4807000,rs6510827）and 22q13.2（rs4822024）are significantly associated with vitiligo in the Chinese Han population.22q13.2（rs4822024）is associated with segmental vitiligo,while 19p13.3（rs4807000,rs6510827）and 22q13.2（rs4822024）are associated with non-segmental vitiligo in the Chinese Han population.Our research suggests that IFIH1,TICAM1,and TEF may be new susceptibility genes for vitiligo in the Chinese Han population.The specific molecular mechanisms need to be cleared by subsequent gene fine-mapping and functional studies.