11q23.3区域白癜风易感基因精细定位研究

Vitiligo is a skin complex disease which may be caused by the interaction of poly-elements such as genetic, immunological and environmental factors. On the basis of the previous genome-wide association studies (GWAS) for vitiligo in Chinese Han population,our group added 272 control samples to the GWAS stage (from 1,117 cases/1,429 controls to 1,117 cases/1,701 controls). Afterwards, the replication studies were performed in multiple independent populations (6,857 cases/12,025 controls)to validate the results of GWAS. It was found that 11q23.3 locus was significantly related to vitiligo (p = 2.47 x 10-9). This region stretches across about 190 kb and contains only two known genes: DDX6 and CXCR5. In this program, we will combine a new technique, i.e.the targeted capture sequence skill, with massively parallel sequencing in order to sequence deeply 11q23.3locus for the purpose of searching on the genetic variations associated directly with vitiligo. In addition to this, we plan to use RT-PCR, Western-Blot, reporter gene experiment and other methods to perform some functional studies on the susceptibility locus for unfolding the mechanism of vitiligo. According to the susceptibility genes, we will further establish a GWAS study cohort to reveal the genetic epidemiology law, occurrence and progress of vitiligo. This study will provide a new theoretical basis for scanning the susceptible populations, finding the genetic targets, going on the risk prediction and clinical therapy, and developing new drugs for vitiligo.

白癜风是一种由遗传、免疫及环境等多因素交互作用所致的皮肤复杂疾病。本课题组在前期白癜风全基因组关联研究（GWAS）的基础上，增加了272例初筛对照样本（1117病例/1701对照），并对先前GWAS结果在多个独立人群（6857病例/12025对照）中进行了验证，结果发现11q23.3位点与白癜风易感性显著关联（p=2.47×10-9）。本研究拟采用新一代靶向捕获序列技术结合大规模平行测序对目标区域11q23.3进行深度测序，搜寻与白癜风发病直接相关的遗传变异，并利用RT-PCR、Western-Blot、报告基因实验等方法对其进行功能研究，以企揭示白癜风的发病机制；进一步针对发现的易感基因建立GWAS研究队列，探讨白癜风遗传流行病学规律及其发生、发展过程。本研究将为筛查白癜风易感人群、寻找遗传靶标、开展疾病风险预测、临床治疗以及新药研发提供新的理论依据。

白癜风为一种由遗传变异、免疫紊乱及环境诱因等多因素交互作用所致的皮肤复杂疾病。本课题组利用前期GWAS研究结果在多个独立人群（6857病例/12025对照）中进行了验证，发现11q23.3位点与中国人群白癜风易感性显著相关（p=2.47×10-9）。该区域包含2个已知基因（DDX6和CXCR5），横跨约190kb序列。通过对该区域进行全基因组数据填补（Imputation），并依据Imputation结果，利用HapMap结合Haploview软件筛选出易感区域內的27个Tag SNP位点。采用Sequenom基因分型技术对该27个Tag SNP点进行分型，通过PLINK分析软件对填补后的全基因组数据进行分析，初步获得了与白癜风相关的阳性SNP位点（rs147473566，rs537080，rs638893）。针对初筛中发现的阳性变异位点，进一步利用Sanger ABI3730测序平台在另外3008白癜风病例和4048对照的独立样本中进行验证，确认了白癜风的风险变异或易感基因，结合临床信息在11q23.3区域内构建了白癜风基因型-表型数据库（数据尚未发表）。本研究结果为搜寻白癜风遗传靶标、建立疾病的遗传咨询与风险预测、以及基因诊断平台奠定了基础。