Genotyping the NPF Biobank for Psoriasis Susceptibility Genes

描述(由申请人提供)： NPF生物库牛皮癣易感基因的基因分型这项应用解决了广泛的挑战领域(08)基因组学和特殊挑战领域：08-AR-101风湿、皮肤和肌肉骨骼疾病现有队列的基因分型。牛皮癣是一种常见的、免疫介导的皮肤和关节疾病，具有很强的遗传基础。为了确定银屑病的易感基因，我们在遗传协会信息网(GAIN)的支持下，参加了银屑病协作性协会研究(CASP)。在一项全基因组关联研究中，我们与圣路易斯华盛顿大学和犹他大学的合作者一起，在1,409例欧洲银屑病患者和1,436名对照中测试了438,670个单核苷酸多态(SNPs)。在5048名银屑病患者和5041名对照中，对代表18个基因座的21个SNPs进行了跟踪调查，这些SNPs显示了GWAS中有希望的关联证据。已证实关联的基因座编码人类白细胞抗原-C，三个参与IL-23信号转导的基因(IL23A、IL23R和IL12B)，两个作用于肿瘤坏死因子-β下游并调节核因子-β信号转导的基因(TNIP1和TNFAIP3)，以及一组参与调节Th2免疫反应的基因(IL4和IL13)。这些结果支持了免疫调节基因与银屑病相关的假设，并支持了还有更多的银屑病易感基因有待识别的假设。我们目前正在对3263例患者、2781名对照和832名家庭成员中的8000多个SNPs进行更广泛的跟踪研究。这项分析将对PSORS1和其他已证实的牛皮癣基因座进行精细定位，并将测试来自最初的GWA5,000个额外的有希望的遗传信号。国家牛皮癣基金会(NPF)建立了维克托·亨舍尔生物库，以确定牛皮癣的易感基因。这项ARRA挑战赠款申请的目标是利用这一杰出的NPF临床和遗传资源，以及密歇根大学牛皮癣遗传学实验室提供的其他样本，以确定牛皮癣和牛皮癣关节炎的其他易感基因，并使结果迅速和广泛地供其他科学家分析。为了实现这一目标，我们提出了以下具体目标：1.从NPF Victor Henschel生物库和密歇根大学银屑病遗传学实验室对CASP深入后续研究中发现的7,600个SNP进行至少1,500个新病例和1,500个新对照的分型。2.一旦质量控制检查完成，将详细的临床表型以及将在目标1中进行的基因分型的结果存储在基因类型和表型数据库(DBGaP)中，并单独分析这些数据，并与现有的数据集一起分析这些数据与银屑病的关联。牛皮癣是一种常见的皮肤和关节炎症性疾病，影响着400多万美国人。它的原因还不是很清楚。识别增加牛皮癣风险的基因将帮助我们解开这种令人困扰的疾病的秘密，并确定更具体和有效的治疗目标。

DESCRIPTION (provided by applicant): Genotyping the NPF Biobank for Psoriasis Susceptibility Genes This application addresses broad Challenge Area (08) Genomics and Specific Challenge Area: 08-AR-101 Genotyping of Existing Cohorts in Rheumatic, Skin, and Musculoskeletal Diseases. Psoriasis is a common, immunologically-mediated disease of the skin and joints, with a strong genetic basis. In an effort to identify psoriasis susceptibility genes, we participated in the Collaborative Association Study of Psoriasis (CASP) with support from the Genetic Association Information Network (GAIN). Together with collaborators from Washington University at St. Louis and the University of Utah, we tested 438,670 single- nucleotide polymorphisms (SNPs) in 1,409 European ancestry psoriasis cases and 1,436 controls in a genome-wide association study (GWAS). Twenty-one SNPs representing 18 loci showing promising evidence of association in the GWAS were followed-up in 5,048 psoriasis cases and 5,041 controls. The loci with confirmed association encode HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R and IL12B), two genes that act downstream of TNF-¿ and regulate NF-¿B signaling (TNIP1 and TNFAIP3), and a set of genes involved in the modulation of Th2 immune responses (IL4 and IL13). These results support the hypothesis that immunoregulatory genes are associated with psoriasis, and support the hypothesis that many more psoriasis susceptibility genes remain to be identified. We are currently carrying out a much more extensive follow-up study of over 8,000 SNPs in 3,263 cases, 2781 controls, and 832 family members. This analysis will fine-map PSORS1 and the other confirmed psoriasis loci, and will test ~5,000 additional promising genetic signals from the initial GWAS. The National Psoriasis Foundation (NPF) has established the Victor Henschel Biobank for the purpose of confirming psoriasis susceptibility loci. The goal of this ARRA Challenge Grant application is to utilize this outstanding NPF clinical and genetic resource, together with additional samples provided by the U-M Psoriasis Genetics Laboratory, to identify additional susceptibility genes for psoriasis and psoriatic arthritis, and to make the results rapidly and widely available for analysis by other scientists. In pursuit of this goal, we propose the following specific aims: 1. To type at least 1,500 new cases and 1,500 new controls from the NPF Victor Henschel Biobank and the U-M Psoriasis Genetics Laboratory for 7,600 SNPs identified as promising from the CASP deep follow-up study. 2. To deposit detailed clinical phenotypes as well as the results of the genotyping to be performed in Aim 1 in the database of Genotypes and Phenotypes (dbGAP) as soon as quality control checks are complete, and to analyze these data for association with psoriasis separately and together with existing datasets. 1 Psoriasis is a common inflammatory disease of the skin and joints, affecting over 4 million Americans. Its cause is not well understood. Identification of genes that increase risk of psoriasis will help us unlock the secrets of this troubling disease, and identify targets for more specific and effective therapy.