Genetic and Genomic Dissection of Psoriatic Arthritis

描述(申请人提供)：牛皮癣关节炎(PSA)是炎症性/自身免疫性关节疾病中的独特之处，因为它的发病通常先于皮肤牛皮癣(PSC)。对于预测生物标记物以确定约25%的银屑病患者中的哪一个将发展为PSA，有一个主要的未得到满足的需求。此外，PSC和PSA表现出严重的威胁生命的共同发病率，特别是心血管疾病。在过去的八年里，我们在密歇根收集了634名PSA患者，其中545人已经接受了全基因组关联研究(GWAS)。国际银屑病关节炎研究小组(IPart)收集了1215名PSA患者的DNA样本，其中1062人已经接受了GWA。基本上，所有这些PSA样本都已经有了广泛的临床随访(平均6.7年)。对现有银屑病GWA和免疫芯片数据的荟萃分析使已知的起源于欧洲的牛皮癣基因座数量增加到至少32个，我们最近完成的1,442例PSA患者与1,433名正常对照的GWA显示出不同于HLA-CW6的强烈的MHC I/III关联信号，以及多个非MHC基因座的全基因组意义，包括IL12B、TNFAIP3、TNIP1和TYK2，以及TRAF3IP2。然而，这些信号只占PSA遗传率的相对较小的一部分，可能至少部分是由于罕见的致病变异的存在。因此，为了进一步剖析iPart的遗传学和生物学，我们提出了以下具体目标：(1)通过(A)支持当前iPart资源的关键核心元素，(B)根据iPart协议扩大密歇根州纵向队列，以及(C)利用社交网络通过患者自我报告增加样本量，以维持和扩大我们的纵向临床资源；以及(D)验证 IPart主题中的此资源。(2)利用1000个基因组测序数据开发的外显子组变异微阵列，对4,450例PSA、3,600例PSC和11,800例正常对照进行基因分型，以确定PSA和PSC的罕见遗传易感性。(3)开发PSV患者PSA发生、疾病亚型、药物反应性和合并症的生物标志物。这将通过对以下各项的RNA分离和RNAseq转录组分析来实现：(A)研究开始时存储的血液样本，这些样本将与发生PSA时发生的PSA病例的额外血液和皮肤样本配对；(B)另外70例确诊PSC病例和70例确诊PSA病例的血液和皮肤横断面样本；以及(C)遗传和基因组数据与(I)针对肿瘤坏死因子和IL-23/IL-17轴的生物制剂的医生评估和患者报告的反应的相关性，(Ii)轴性与外周PSA和指甲受累，以及(Iii)包括肥胖和心血管疾病在内的系统性共病。相关性：PSA是美国的一个主要健康问题。使患者倾向于PSA和PSC的机制尚不清楚。这项拟议的研究将利用全基因组关联研究、转录组分析和世界上最大的PSA纵向资源来解决我们在PSA及其相关共病的机制理解方面的一个主要差距。这项研究的结果也可能与其他自身免疫性疾病相关。

DESCRIPTION (provided by applicant): Psoriatic arthritis (PsA) is distinctive amongst the inflammatory/autoimmune joint diseases in that its onset is commonly preceded by cutaneous psoriasis (PsC). There is a major unmet need for predictive biomarkers to determine which of the ~25% of psoriasis patients will develop PsA. Moreover, PsC and PsA exhibit significant life-threatening co-morbidity, notably from cardiovascular disease. Over the past eight years, we have collected 634 PsA patients at Michigan, 545 of whom have already been subjected to genome-wide association studies (GWAS). The International Psoriatic Arthritis Research Team (IPART) has collected DNA samples from 1,215 PsA patients, 1,062 of which have already been subjected to GWAS. Essentially all of these PsA samples already have extensive clinical follow-up (mean 6.7 years). Meta-analysis of existing GWAS and Immunochip data for psoriasis has increased the number of known European-origin psoriasis loci to at least 32, and our recently completed GWAS of 1,442 PsA cases vs. 1,433 normal controls reveals a strong MHC Class I / III association signal distinct from HLA-Cw6 as well as genome- wide significance for multiple non-MHC loci including IL12B, TNFAIP3, TNIP1, and TYK2, and TRAF3IP2 . However, these signals account for only a relatively small fraction of the heritability of PsA, likely due a least in part to the existence of rare disease-predisposing variants. Therefore, to further dissec the genetics and the biology of, we propose the following specific aims: (1) To maintain and expand our longitudinal clinical resource by (a) supporting critical core elements of the current IPART resource, (b) expanding the Michigan longitudinal cohort under the IPART protocol and (c) utilizing social networking to increase sample size via patient self-report; and (d) validating this resource in IPART subjects. (2) To identify rare genetic susceptibility variants for PsA and PsC, making use of an innovative exome variation microarray developed from 1000 Genomes Project sequencing data to genotype 4,450 PsA cases, 3,600 PsC cases, and 11,800 normal controls. (3) To develop biomarkers for PsA development, disease subtypes, drug responsiveness, and co-morbidities in PsV patients. This will be accomplished by RNA isolation and RNASeq transcriptome analysis of (a) blood samples stored at study entry, which will be paired with additional blood and skin samples from incident PsA cases at the onset of PsA development; (b) a cross- sectional sample of blood and skin from 70 additional definite PsC cases and 70 definite PsA cases; and (c) correlation of genetic and genomic data with (i) physician-assessed and patient-reported responses to biologics targeting the TNF and IL-23/IL-17 axes, (ii) axial vs. peripheral PsA and nail involvement, and (iii) systemic co-morbidities including obesity and cardiovascular disease. RELEVANCE: PsA is a major health problem in the United States. The mechanisms that predispose patients to PsA vs. PsC are unknown. The proposed research will utilize the power of genome-wide association studies, transcriptome analysis, and the largest longitudinal resource of PsA in the world to address a major gap in our mechanistic understanding of the causes of PsA and its associated co-morbidities. The results of this research are also likely to be relevant to other autoimmune diseases.