Genotyping the NPF Biobank for Psoriasis Susceptibility Genes

描述（由申请人提供）： 对NPF生物库中的银屑病易感基因进行基因分型此应用程序解决了广泛的挑战领域（08）基因组学和特定挑战领域：08-AR-101风湿性、皮肤和肌肉骨骼疾病中现有队列的基因分型。银屑病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。为了确定银屑病易感基因，我们在遗传关联信息网络（GAIN）的支持下参与了银屑病协作关联研究（CASP）。我们与来自圣路易斯华盛顿大学和犹他州大学的合作者一起，在全基因组关联研究（GWAS）中对1，409例欧洲血统银屑病病例和1，436例对照进行了438，670个单核苷酸多态性（SNP）检测。代表18个位点的21个SNP在GWAS中显示出有希望的关联证据，在5，048例银屑病病例和5，041例对照中进行了随访。已证实相关的基因座编码HLA-C、参与IL-23信号传导的三个基因（IL 23 A、IL 23 R和IL 12 B）、作用于TNF-α下游并调节NF-α B信号传导的两个基因（TNIP 1和TNFAIP 3）以及参与调节Th 2免疫应答的一组基因（IL 4和IL 13）。这些结果支持免疫调节基因与银屑病相关的假设，并支持更多银屑病易感基因有待鉴定的假设。我们目前正在对3,263例病例、2781例对照和832名家庭成员中的8,000多个SNP进行更广泛的随访研究。这项分析将精细定位PSORS 1和其他确认的银屑病位点，并将测试来自初始GWAS的约5，000个额外的有希望的遗传信号。国家银屑病基金会（NPF）建立了维克托亨舍尔生物样本库，目的是确定银屑病易感基因位点。这项ARRA挑战资助申请的目标是利用这一杰出的NPF临床和遗传资源，以及U-M银屑病遗传学实验室提供的额外样本，以确定银屑病和银屑病关节炎的额外易感基因，并使结果迅速和广泛地供其他科学家分析。为实现这一目标，我们提出以下具体目标：1.对来自NPF维克托亨舍尔生物库和密歇根大学遗传学实验室的至少1,500例新病例和1,500例新对照进行分型，以获得CASP深度随访研究中确定为有希望的7,600个SNP。2.一旦完成质量控制检查，就将详细的临床表型以及目标1中待进行的基因分型结果存款基因型和表型数据库（dbGAP），并单独分析这些数据与银屑病的相关性，以及与现有数据集一起分析这些数据。牛皮癣是一种常见的皮肤和关节炎性疾病，影响超过400万美国人。其原因尚不清楚。鉴定增加银屑病风险的基因将有助于我们解开这种令人不安的疾病的秘密，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.