Genome-Wide SNP Association in Psoriasis

描述（由申请人提供）：银屑病（Ps）是一种常见的慢性炎症性皮肤病，影响约2-3%的欧洲血统个体。10-40%的时间它伴随着致残性银屑病关节炎（PsA）。其他合并症包括代谢综合征和心血管疾病和中风的风险增加。全基因组关联研究已经确定了20多个易感基因座，但占疾病遗传率的不到20%。最近，我们使用了连锁分析和NexGen测序相结合，以确定突变的半胱天冬酶募集结构域蛋白14（CARD 14）在两个家庭的高度渗透形式的Ps和PsA，从而成功地确定了PSORS 2基因座上的人类染色体17 q25。对超过5,000例病例和对照的筛查显示CARD 14中存在额外的罕见变异，并且病例与对照相比存在过量的变异。我们还确定了一个单一的严重银屑病的情况下，从头突变CARD 14。Ps/PsA相关突变增强了NF-kB活化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。在本申请中，我们将在Ps/PsA患者和对照的扩展队列中扩展我们的CARD 14的遗传分析。我们还将对散发性和家族性Ps和PsA的病例进行外显子组捕获或全基因组测序，以筛选具有罕见的高渗透变异的易患疾病的其他基因。通过靶向Ps和PsA的病例或家族，我们希望减少可能的遗传异质性。将根据已知的生物学作用/Ps/PsA中改变的途径或如果它们富集有害变体，对基因进行优先级排序以进行随访。这些基因中的其他变体将被 通过靶向捕获鉴定（每年4个基因）。病例与对照相比具有额外变异的那些将在> 5，000例病例和5，000例对照的较大队列中进行基因分型。然后进行统计分析以检查特定基因中的罕见变异对Ps和PsA易感性的贡献。将进行新变体的功能研究，以补充遗传研究。通过鉴定导致这些疾病的罕见的高渗透突变，我们将增加我们对疾病发病机制的理解，并确定新的治疗靶点，这些靶点位于Ps/PsA改变的通路内。

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.