MHC and KIR Region Genomics in Psoriasis

银屑病的 MHC 和 KIR 区域基因组学

基本信息

批准号：
9308668
负责人：
Wilson Liao
金额：
$ 70.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-24 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308668
关键词：
Accounting Address Affect Alleles American Arthritis Asians Autoimmune Diseases Bioinformatics Cells Cohort Studies Comorbidity Conflict (Psychology)DNA sequencing Data Data Set Development Digit structure Disease Disease Progression Disease susceptibility Ethnic group European Exhibits Flow Cytometry Genes Genetic Genetic Models Genetic Variation Genetic study Genomic Segment HLA-C Antigens Immune Immunogenetics Immunoglobulins Immunologist Individual Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-12 International Killer Cells Lead Ligands Light Linkage Disequilibrium Major Histocompatibility Complex Major Histocompatibility Complex Gene Mediating Methods Mica Modeling Myocardial Infarction Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Outcome Pathogenesis Pathway interactions Patients Population Predisposition Problem Solving Protocols documentation Psoriasis Psoriatic Arthritis Receptor Gene Refractory Reporting Research Design Residual state Resolution Role SNP array SNP genotyping Sample Size Severities Signal Transduction Skin Stroke Susceptibility Gene Systemic disease Systems Biology TNF gene Techniques Technology Time United States Variant Work cohort cost deep sequencing genetic association genetic variant genome wide association study improved innovation insertion/deletion mutation multidisciplinary next generation sequencing novel novel therapeutics population health public health relevance receptor response skin disorder tool transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Psoriasis is a common, immune-mediated, inflammatory skin disease associated with arthritis and systemic inflammation. Genome-wide association studies of psoriasis have identified over 40 susceptibility loci implicating both innat and adaptive immune pathways. The genetic locus exhibiting the greatest association with psoriasis is the MHC, with HLAC:06:02 showing very strong association in multiple ethnic groups. However, significant residual genetic signal remains in the MHC after accounting for the effects of HLAC:06:02 and it is not clear whether the residual signal resides in other HLA alleles, additional nearby genes, or regulatory variants. There is also evidence to suggest psoriasis susceptibility may be influenced by the interaction of killer cell immunoglobulin-like receptors (KIR) with HLA class I ligands; however, studies to date of HLA-KIR in psoriasis have generally been hampered by the time-consuming nature and high cost of HLA and KIR typing. Finally, although HLAC:06:02 is known to associate significantly with psoriasis and HLAC:06:02-positive psoriasis patients show differences in disease onset, severity, and response to therapy compared to HLAC:06:02-negative psoriasis patients, the mechanism by which HLAC:06:02 contributes to psoriasis has not been well studied. In this application, we utilize a variety of innovative approaches to address these questions. First, we perform high fidelity next-generation sequencing of the extended MHC in a psoriasis reference cohort and impute identified variants into European and Asian GWAS cohorts totaling over 8,500 cases and 17,000 controls. We construct a comprehensive genetic model to best explain the genetic association within the MHC using multiple model inputs including 4-digit resolution calls for 26 HLA/MICA/MICB/TAP genes, SNPs, indels, and functional variables. Second, we optimize a novel KIR imputation method that uses SNP array data to accurately call KIR copy number and apply this method to examine HLA-KIR associations in psoriasis using a large cohort. Finally, we utilize a novel flow cytometry protocol to sort psoriasis-relevant cell populations from the ski of HLAC:06:02-positive and HLAC:06:02- negative psoriasis patients, perform whole transcriptome RNA-sequencing on individual cell populations, and use systems biology analytical approaches to better understand the contribution of HLAC:06:02 to psoriasis pathogenesis. Together, the proposed work will identify causal variants in psoriasis, shed light on functional mechanisms, and potentially identify novel therapeutic pathways. The approaches and tools developed here will greatly facilitate the study of other immune-mediated diseases.

描述（由申请人提供）：银屑病是一种常见的、免疫介导的炎症性皮肤病，与关节炎和全身炎症相关，银屑病的全基因组关联研究已确定了 40 多个涉及先天性和适应性免疫途径的易感基因座。与银屑病表现出最大关联的是 MHC，HLAC:06:02 在多个种族群体中表现出非常强的关联，但仍存在显着的残留遗传信号。在考虑了 HLAC:06:02 的影响后仍保留在 MHC 中，并且尚不清楚残留信号是否存在于其他 HLA 等位基因中，还有证据表明，杀伤细胞免疫球蛋白样受体 (KIR) 与 HLA I 类配体的相互作用可能会影响银屑病的易感性；然而，迄今为止的 HLA-KIR 在银屑病中的研究表明。最后，尽管 HLAC:06:02 已知与牛皮癣和牛皮癣显着相关，但通常受到 HLA 和 KIR 分型的耗时性和高成本的阻碍。与 HLAC:06:02 阴性银屑病患者相比，HLAC:06:02 阳性银屑病患者在疾病发作、严重程度和治疗反应方面存在差异，HLAC:06:02 导致银屑病的机制尚未得到充分研究在此应用中，我们利用各种创新方法来解决这些问题，首先，我们对银屑病参考队列中的扩展 MHC 进行高保真下一代测序。我们使用多个模型输入（包括 26 个 HLA/MICA/MICB/ 的 4 位分辨率调用）将已识别的变异归入欧洲和亚洲 GWAS 队列中，总计超过 8,500 个病例和 17,000 个对照。其次，我们优化了一种新颖的 KIR 插补方法，该方法使用 SNP 阵列数据来准确调用 KIR 拷贝数并应用该方法。使用大型队列检查 HLA-KIR 与银屑病的关联最后，我们利用一种新的流式细胞术方案从 HLAC:06:02 阳性和 HLAC:06:02 阴性银屑病患者的皮肤中对银屑病相关细胞群进行分类。，对单个细胞群进行全转录组 RNA 测序，并使用系统生物学分析方法更好地了解 HLAC:06:02 对银屑病的贡献总之，拟议的工作将确定牛皮癣的因果变异，阐明功能机制，并可能确定新的治疗途径，这里开发的方法和工具将极大地促进其他免疫介导疾病的研究。