银屑病5q15易感区域功能性变异搜寻及生物学作用网络构建

Psoriasis is a common relapsing and remitting skin disease, which severely affected physical and mental health of patients. The applicant has been working on the research of the pathogenesis of psoriasis for 10 years. Under the support of Young Scientist's Fund, we identified that the LNPEP gene may be involved in MHC class I molecules antigen presenting or the NF-κB signaling pathway for psoriasis by several different ways, such as gene genotyping, gene expression, path analysis and so on. Then we collected 20 pairs of lesions and non-lesions in each patient and 20 skin tissues of the controls to perform the whole genome expression analysis, and found that the expression of LNPEP in skins was significantly associated with psoriasis（P=3×10-15）. Based on three databases of genome-wide genotyping, exome sequencing and whole genome expression profiling, with more than ten thousand data information, This study plans to take 1000 Genomes data for reference, carry out imputation in 5q15 that LNPEP was located for the key susceptibility genes using IMPUTE2 software, search for the functional variants by conducting gene sequencing with replication in a large number of samples (5000 cases and 5000 controls), establish gene-gene biological interaction network verified by gene co-expression analysis, and then build the genetic risk prediction model, which will help to apply basic theory achievement to translational medicine, and also will be a valuable breakthrough of the target identification for the disease diagnosis and treatment in the future.

银屑病易复发、难根治，严重影响患者身心健康。申请人从事银屑病发病机制研究十年，在青年基金资助下，从基因分型、基因表达、通路分析等多角度证实LNPEP可能参与MHC I类分子抗原提呈或NF-κB信号通路影响疾病发生。收集20对患者皮损/非皮损组织及20例对照组织开展全基因组表达谱预实验，发现LNPEP在组织中表达与银屑病显著相关（P=3×10-15）。本课题基于前期疾病全基因组基因分型、全外显子测序及组织基因表达谱数据库万余例数据，拟以千人基因组数据为参考，采用Impute2软件，对LNPEP所在5q15区域行基因填补（Imputation），筛选关键基因；开展基因测序搜寻功能性致病变异；并在大样本人群中验证（5000- 5000），建立基因间生物学交互作用网络，从基因共表达研究功能学角度加以验证，并构建多基因风险预测模型，力求将基础理论成果应用于转化医学，为疾病诊断治疗靶标筛查提供突破口。

银屑病易复发、难根治，严重影响患者身心健康。课题组基于前期对银屑病全基因组基因分型、全外显子组、靶向测序和验证数据联合分析的基础上，在5q15区域开展功能性致病变异搜寻研究，发现本课题研究区域(5q15)等区域内25个基因的外显子插入缺失(InDels)，解释了大约1.29%的银屑病遗传度；探寻到5q15区域的ERAP1基因上6个SNPs和几种单倍型与汉族人银屑病相关，提示是ERAP1银屑病的关键易感基因，单倍型分析提示几种特殊单倍型有预测疾病的功能；揭示了5q15区域ERAP1和HLA及MIR548AZ和TYK2的交互作用在银屑病发病中重要作用，构建了基因间生物学交互作用网络，提示免疫系统和抗原加工途径在银屑病发病机制中发挥重要作用。同时课题组还对5q15周围区域与银屑病相关的易感变异展开搜寻，发现ADRA1B基因变异不仅与中国人群银屑病有关，还与中重度银屑病及银屑病发病年龄早的临床亚型相关，为完善生物学作用网络构建提供了更多的遗传信息，开展5q15区域相关的基因型与表型相关性研究，DNA甲基化与银屑病发病相关性研究，力求将基础理论成果应用于转化医学，为银屑病药物靶点研发、疾病预防与诊疗提供新的视角，同时进一步推进了银屑病遗传学研究和精准医学研究进程。