Genetic and Genomic Dissection of Psoriatic Arthritis

描述（由申请人提供）：银屑病关节炎（PsA）在炎性/自身免疫性关节疾病中是独特的，因为其发病通常在皮肤银屑病（PsC）之前。预测生物标志物以确定约25%的银屑病患者中的哪些将发展PsA是一个主要的未满足的需求。此外，PsC和PsA表现出显著的危及生命的共病，特别是心血管疾病。在过去的八年里，我们在密歇根州收集了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）从1,215名PsA患者中收集了DNA样本，其中1,062名患者已经接受了GWAS。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）。 现有银屑病GWAS和免疫芯片数据的荟萃分析将已知欧洲起源银屑病基因座的数量增加到至少32个，我们最近完成的1，442例PsA病例与1，433例正常对照的GWAS显示了与HLA-Cw 6不同的强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IL 12 B，TNFAIP 3，TNIP 1，TYK 2和TRAF 3 IP 2。然而，这些信号仅占PsA遗传性的一小部分，可能至少部分是由于存在罕见的疾病易感变异。 因此，为了进一步剖析的遗传学和生物学，我们提出了以下具体目标：（1）通过（a）支持当前IPART资源的关键核心要素，（B）根据IPART协议扩展密歇根纵向队列，（c）利用社交网络通过患者自我报告增加样本量，（d）验证 在IPART科目中的资源。(2)为了识别PsA和PsC的罕见遗传易感性变体，利用从1000个基因组计划测序数据开发的创新外显子组变异微阵列对4，450例PsA病例，3，600例PsC病例和11，800例正常对照进行基因型分析。(3)开发PsA发展、疾病亚型、药物反应性和PsV患者合并症的生物标志物。这将通过（a）研究进入时储存的血液样品的RNA分离和RNASeq转录组分析来完成，其将与来自PsA发展开始时的偶发PsA病例的额外血液和皮肤样品配对;（B）来自70个额外确诊PsC病例和70个确诊PsA病例的血液和皮肤的横截面样品;和（c）遗传和基因组数据与（i）医生评估和患者报告的对靶向TNF和IL-23/IL-17轴的生物制剂的反应，（ii）轴向vs.外周PsA和指甲受累，和（iii）包括肥胖和心血管疾病的全身性共病的相关性。相关性：PsA是美国的主要健康问题。使患者易患PsA与PsC的机制尚不清楚。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纵向资源的力量，以解决我们对PsA及其相关并发症原因的机械理解的主要差距。这项研究的结果也可能与其他自身免疫性疾病有关。 公共卫生相关性：PsA是美国的一个主要健康问题。使患者易患PsA与PsC的机制尚不清楚。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纵向资源的力量，以解决我们对PsA及其相关并发症原因的机械理解的主要差距。这项研究的结果也可能与其他自身免疫性疾病有关。

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. PUBLIC HEALTH 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.