Genome-Wide SNP Association in Psoriasis

描述(申请人提供)：牛皮癣(Ps)是一种常见的慢性炎症性皮肤病，影响大约2%-3%的欧洲血统个人。10%-40%的时间伴随着致残性牛皮癣关节炎(PSA)。其他并发症包括代谢综合征以及心血管疾病和中风风险的增加。全基因组关联研究已经确定了20多个易感基因，但占疾病遗传性的比例不到20%。我们最近利用连锁分析和NexGen测序相结合的方法，在两个具有高穿透性Ps和PSA的家系中鉴定了caspase招募结构域蛋白14(CARD14)的突变，从而成功地鉴定了人类染色体17q25上的PSORS2基因座。对5,000多例病例和对照的筛查显示，CARD14中还有其他罕见的变异，病例与对照相比有更多的变异。我们还发现了一例CARD14基因去新生突变的严重银屑病病例。PS/PSA相关突变增强了核因子-kB的激活，并改变了角质形成细胞的转录组，导致趋化因子和其他银屑病相关炎症标志物的产生。在目前的应用中，我们将在Ps/PSA患者和对照的扩大队列中扩展我们的CARD14基因分析。我们还将对散发性和家族性Ps和PSA病例进行外显子组捕获或全基因组测序，以筛选更多具有罕见的高渗透性变异的易患疾病的基因。通过针对同时患有Ps和PSA的病例或家系，我们希望减少可能的遗传异质性。将根据Ps/PSA中已知的生物学作用/途径的变化或是否富含有害变异来确定后续基因的优先顺序。这些基因中的其他变异将是 通过目标捕获确定(每年4个基因)。那些在病例和对照中有额外变异的人将在更大的&gt；5000病例和5000对照队列中进行基因分型。然后将进行统计分析，以检查特定基因中的罕见变异对Ps和PSA易感性的影响。将对新变种进行功能研究，以补充遗传研究。通过识别导致这些疾病的罕见的高渗透性突变，我们将增加对疾病发病机制的理解，并确定位于Ps/PSA改变的通路中的新的治疗靶点。

DESCRIPTION (provided by applicant): Psoriasis (Ps) is a common chronic inflammatory skin disease affecting approximately 2-3% of individuals of European ancestry. 10-40% of the time it is accompanied by a disabling psoriatic arthritis (PsA). Other co-morbidities include metabolic syndrome and an increased risk for cardiovascular disease and stroke. Genome-wide association studies have identified over 20 predisposing loci, but account for less than 20% of disease heritability. We recently used a combination of linkage analysis and NexGen sequencing to identify mutations in caspase recruitment domain protein 14 (CARD14) in two families with highly penetrant forms of Ps and PsA, thereby successfully identifying the PSORS2 locus on human chromosome 17q25. Screening of over 5,000 cases and controls revealed additional rare variants in CARD14 and an excess of variants in cases versus controls. We also identified a single severe psoriasis case with a de-novo mutation in CARD14. Ps/PsA associated mutations enhanced NF- kB activation and altered the transcriptome of keratinocytes, leading to the production of chemokines and other psoriasis-associated inflammatory markers. In the current application we will extend our genetic analyses of CARD14 in an extended cohort of Ps/PsA patients and controls. We will also perform exome capture or whole genome sequencing on cases with sporadic and familial forms of Ps and PsA to screen for additional genes with rare highly penetrant variants predisposing to disease. By targeting cases or families with both Ps and PsA we hope to reduce possible genetic heterogeneity. Genes will be prioritized for follow up on the basis of known biological roles/pathway altered in Ps/PsA or if they are enriched for deleterious variants. Additional variants in these genes will be identified with targeted capture (4 genes per year). Those with additional variants in cases versus controls will be genotyped in a larger cohort of >5,000 cases and 5,000 controls. Statistical analyzes will then be performed to examine the contribution of rare variants in specifi genes to Ps and PsA susceptibility. Functional studies of novel variants will be performed to complement the genetic studies. By identifying rare highly penetrant mutations leading to these diseases, we will increase our understanding of disease pathogenesis and identify novel therapeutic targets lying within pathways altered in Ps/PsA.