Genome-Wide SNP Association in Psoriasis

描述（由申请人提供）：牛皮癣（Ps）是一种常见的慢性炎症性皮肤病，影响约2-3%的欧洲血统个体。10-40%的时间伴有致残性银屑病关节炎（PsA）。其他合并症包括代谢综合征以及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多个易感位点，但占疾病遗传性的比例不到20%。我们最近使用连锁分析和NexGen测序相结合的方法，在两个具有高外显形式的Ps和PsA的家族中鉴定了caspase募集结构域蛋白14 （CARD14）的突变，从而成功地鉴定了人类染色体17q25上的PSORS2位点。对超过5000例病例和对照的筛查显示，CARD14中有额外的罕见变异，病例与对照中有多余的变异。我们还发现了一个严重的牛皮癣病例，CARD14发生了去新生突变。Ps/PsA相关突变增强了NF- kB的激活，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患者和对照组的扩展队列中扩展CARD14的遗传分析。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，以筛选具有易患疾病的罕见高渗透变异体的其他基因。通过针对同时患有Ps和PsA的病例或家庭，我们希望减少可能的遗传异质性。基因将根据已知的生物学作用/Ps /PsA改变的途径或它们是否因有害变异而富集而优先进行后续研究。这些基因的其他变异将会

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.