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。 公共卫生相关性：牛皮癣和牛皮癣关节炎是皮肤和关节的慢性炎症性疾病，目前还没有治愈方法。直接和间接医疗保健总额 每年的成本约为112.5亿美元，其中工作损失占成本负担的40%。牛皮癣可以导致与其他主要疾病一样的残疾，包括糖尿病、心脏病、高血压和抑郁症，并伴有自杀念头。它与许多共同的疾病，如肥胖、代谢综合征、糖尿病、心血管疾病、肾功能衰竭、非酒精性脂肪肝、克罗恩病、高血压、中风和高血压密切相关。目前的治疗方法对患者和他们的医疗保健提供者来说是一个挑战，因为没有一种治疗方法对每个人都有效，一些治疗方法随着时间的推移而失去效果，许多治疗方法与其他治疗方法结合使用，并且所有治疗方法都与一系列独特的副作用相关。目前这项研究的目标是识别导致这些疾病的罕见突变，从而增加我们对它们的遗传基础和改变的途径的了解。这些有望为这些毁灭性疾病的治疗提供新的靶点。

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. PUBLIC HEALTH RELEVANCE: Psoriasis and psoriatic arthritis are chronic inflammatory diseases of the skin and joints for which there are no cures. Total direct and indirect health care costs are ~ $11.25 billion annually with work loss accounting for 40% of the cost burden. Psoriasis can cause as much disability as other major diseases, including diabetes, heart disease, hypertension and depression accompanied by thoughts of suicide. It goes hand-in- hand with myriad co-morbid conditions such as obesity, metabolic syndrome, diabetes, cardiovascular disease, renal failure, non-alcoholic fatty liver disease, Crohn's disease, hypertension, stroke, and hypertension. Current treatments present a challenge for patients and their health care providers because no one treatment works for everyone, some treatments lose effectiveness over time, many treatments used are in combination with other treatments, and all treatments are associated with a unique set of side effects. The goal of the current study is to identify rare mutations leading to these diseases, thereby increasing our understanding of their genetic basis and their altered pathways. These are expected to provide novel targets for therapies for these devastating diseases.