Genetic and Genomic Dissection of Psoriatic Arthritis

描述（由申请人提供）：银屑病关节炎（PsA）在炎症/自身免疫性关节疾病中是独特的，因为它的发病通常先于皮肤银屑病（PsC）。对于预测性生物标志物的需求尚未得到满足，以确定约25%的牛皮癣患者中哪一个会发展为PsA。此外，PsC和PsA表现出严重的危及生命的合并症，特别是心血管疾病。在过去的八年中，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GWAS治疗。基本上所有这些PsA样本都已经进行了广泛的临床随访（平均6.7年）。对银屑病现有GWAS和免疫芯片数据的荟萃分析已将已知的欧洲来源银屑病基因座的数量增加到至少32个，我们最近完成的1442例PsA病例与1433例正常对照的GWAS显示出与HLA-Cw6不同的强烈MHC I / III类关联信号，以及多个非MHC基因座的全基因组意义，包括IL12B、TNFAIP3、TNIP1、TYK2和TRAF3IP2。然而，这些信号只占PsA遗传能力的一小部分，可能至少部分是由于罕见疾病易感变异的存在。因此，为了进一步分析遗传和生物学，我们提出以下具体目标：(1)通过(a)支持当前IPART资源的关键核心要素，(b)扩大IPART协议下的密歇根纵向队列，(c)利用社交网络通过患者自我报告增加样本量来维持和扩大我们的纵向临床资源；(d)验证

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.