中国汉族人特应性皮炎易感基因FLG的精细定位与功能研究

特应性皮炎（AD）是一种常见的慢性复发性炎症性皮肤病，常伴剧烈瘙痒，严重影响患者身心健康。申请人读研期间所在单位通过全基因组关联研究发现FLG基因与AD相关，申请人在此基础上进行深入研究，鉴定出FLG变异位点C.3321delA，基因型-表型的相关性分析结果表明该突变与AD的多种伴发症相关。然而该基因区域复杂，目前国内外已报道了60多个不同的FLG变异位点，但真正的功能性致病变异位点尚未明确。为了鉴定出FLG基因与汉族人AD易感性真正关联的致病变异位点，并揭示其在AD发病中的相关作用机制，本项目拟采用新一代测序技术对FLG区域进行高覆盖度测序并构建单倍型参考模板,在前期基因分型数据基础上进行基因型推算(imputation)，利用Sequenom基因分型在独立样本中验证，通过这种精细定位的方法筛选出真正的致病变异，并从变异位点水平、基因水平对其开展功能学研究，最终鉴定出FLG区域真正的功能

Atopic dermatitis (AD) is a common chronic relapsing, inflammatory skin disorder,often accompanies with severe pruritus, which may severely affect patients’physical and mental health. The proposer’s institution at the graduate level have found that FLG was associated with AD through a genome-wide association study.Based on which, the proposer performed an in-depth study,identified a FLG variant C.3321delA, and carried out genotype-phenotype associated analysis which revealed that the variant C.3321delA was associated with several complications of AD. However，the FLG region is complex.To date,over 60 variants of FLG have been reported around the world，but the true functional causal variants of FLG remain unclear.In order to identify the causal variants within FLG and reveal the potential roles in the mechanism of AD in Han Chinese population,we plan to perform high overlay sequencing within FLG using new sequencing technique and build the haploid reference template. We will perform genotype imputation analysis based on the previous data, Sequenom validation with another sample for FLG, and screen out the true causal variants by this fine mapping way. In addition, a series of functional studies on the identified causal variants at variant and gene levels will also be performed to make sure the true causal variants of FLG gene for AD, and it will provide a new theoretical basis for genetic pathogenesis of AD.