关节型、脓疱型和寻常型银屑病易感位点差别研究

Psoriasis vugaris affects more than 80% psoriatic patients. Although psoriatic arthritis and generalized pustular psoriasis affect less than 20% psoriatic patients, their clinical manifestations were more serious. Recently genome-wide associaation studies and exom sequence have identified more than 40 susceptibility loci, 5 common single-nucleotide variants (SNVs) and 2 rare SNVs for psoriasis, including TH17 pathway, IL23A\NF-KB pathway and TH2pathway. Many susceptiility genes have been used as target of biological treatment of psoriasis vugaris. But gene analysis of other subtypes of psoriasis were relatively rare. There were only 2 psoriatic arthritis GWASs. Most susceptibility loci were in accordance with psoriasis, in contrast, the susceptibility loci of generalized pustular psoriasis was IL36RN. IL36RN didn't show any association with other subtypes of psoriasis. In this study, we aim to perform candidate gene analysis for psoriatic arthritis and generalized pustular psoriasis using sequenom platform. The different and common loci will be disscussed in this study. Then we will use pathway analysis, gene-gene interaction analysis and genotype-phenotype analysis to explore the potential function of these loci. This study will lay the foundation for further study in subtypes of psoriasis pathogenesis and effective treatment.

寻常型银屑病占银屑病的80%以上，脓疱型、关节炎型、红皮病型银屑病尽管不足20%，但临床表现更加严重、治疗效果差。近年来通过全基因组关联分析和外显子测序发现寻常型银屑病易感基因达40余种，促进了对寻常型银屑病发病机制中遗传易感性的认识，许多易感基因已经成为银屑病生物治疗的靶点。尽管也发现IL12B和HLA-C与关节炎型银屑病相关，IL36RN与脓疱型银屑病相关。但其他亚型银屑病的遗传易感性知之甚少，本课题拟用Sequenom和测序平台，研究脓疱型和关节炎型银屑病是否存在寻常型银屑病的共同易感基因，关节炎型银屑病是否存在类风湿性关节炎、强直性脊柱炎的共同易感基因，找出三种亚型银屑病易感基因的差别。通过基因相互作用研究，基因与表型关系研究，疾病基因生物学通路研究等为关节炎型和脓疱型银屑病的遗传易感性提供证据，也为银屑病亚型生物靶向治疗研究提供方向。

本项目旨在通过候选用Sequenom基因分型平台，研究脓疱型和关节炎型银屑病是否存在寻常型银屑病的共同易感基因，找出三种亚型银屑病易感基因的联系与差别。为治疗研究提供方向。 .本研究发现了3个关节型银屑病显著位点，7个潜在相关位点，最显著位点位于在5q33.3， IL12B为此区域候选基因。另一显著位点为1p36，此区域仅有一个基因为RUNX3，RUNX3与CD8+ T淋巴细胞分化相关。此外位于1q21.3 的SNP rs1886734也被证实与关节型银屑病相关。使用permutation 检验，矫正后P值依然显著。我们使用非参 MDR 寻找基因间相互作用模式，发现SNPs rs1886734 与 rs7709212是关节型银屑病相关最佳互作模式。在脓疱型银屑病候选基因研究中，我们发现2个脓疱型银屑病相关位点和1个提示位点。最显著的位点位于5q33.1。此区域包含2个基因：TNIP1 和ANAA6。IPA分析发现此区域有3个有显著意义pathway可被注释到TNIP1上。因此我们推断TNIP1为此区域相关基因。另一个显著位点为rs3813063，此区域基因为CARD14。此外我们还发现了提示显著性位点为rs10088247。此区域只有一个基因CSMD1， 为表皮或者上皮的肿瘤抑制基因。最后，我们发现上述基因可被注释于一个pathway中。这些研究为后续开展各种亚型银屑病预测，早期诊断，药物疗效和副作用观察，靶向治疗的精准医学研究提供了重要的参考数据。