Integrative Immunogenetics: Towards the Development of an Immune-specific Therapy for Primary Sclerosing Cholangitis

原发性硬化性胆管炎（PSC）是一种罕见的，进行性的，慢性炎症性疾病的肝内和肝外胆管，导致长期炎症和纤维化的胆管。目前，对于PSC没有有效的治疗方法，并且大多数PSC患者由于疾病的进行性而需要肝移植。然而，疾病可能会复发。作为国际PSC研究组（IPSCSG）成员，申请人近年来开展了多项PSC全基因组关联研究（GWAS），共鉴定出23个PSC全基因组显著风险位点。PSC患者迫切需要确定确切的遗传易感性以及对可能的抗原和患者特异性免疫应答的分子理解，以开发个性化治疗。该项目的目标是详细鉴定在疾病相关细胞和组织中驱动PSC发展的实际致病基因、遗传变异和转录本，并鉴定潜在致病的内源性抗原。为此，我们将对人类白细胞抗原区（HLA;染色体6p 21）、免疫球蛋白样受体区（KIR; 19 q13）进行遗传精细定位。42)和22个先前建立的非HLA易感性基因座，使用来自总计3，408名PSC患者和34，213名健康对照的大病例群体的全基因组数据，随后进行HLA-KIR和HLA/非HLA相互作用（上位性）分析。对来自877名德国PSC患者和3，449名健康对照的新生成的全外显子组测序（WES）数据的分析将有助于确定已知易感基因座内外的致病基因和蛋白质编码风险变体。我们将结合药物数据库进行基于网络的计算机筛选，以建议可能用于PSC的候选药物。使用跨组织表达插补模型，通过同时对来自血液、肝脏和肠组织的全基因组测序（WGS）和RNA测序（RNA-seq）数据进行建模，我们将对PSC患者和对照进行全转录组关联研究（TWAS），以促进疾病相关基因的确定。将进行全肽组关联研究（PepWAS）、肽结合预测和肽洗脱实验，以获得877例德国PSC患者和3，449例对照的可能疾病相关内源性肽和计算机模拟免疫肽组。最后，我们正在准备免疫遗传学分析的结果，以便临床研究人员可以进行功能性后续实验并开发新的个体治疗方法。

Primary sclerosing cholangitis (PSC) is a rare, progressive, chronic inflammatory disease of the intra and extrahepatic bile ducts that results in long-term inflammation and fibrosis of the bile ducts. Currently, there is no effective therapy for PSC, and most PSC patients require liver transplantation due to the progressive nature of the disease. Nevertheless, recurrence of the disease may occur. As a member of the International PSC Study Group (IPSCSG), the applicant has conducted several genome-wide association studies (GWAS) for PSC in recent years, identifying a total of 23 genome-wide significant risk loci for PSC. Identification of the exact genetic predisposition as well as a molecular understanding of a possible antigen and patient-specific immune response is urgently needed for PSC patients to develop personalized therapies. The goal of the project is to identify in detail the actual causative genes, genetic variants and transcripts that drive the development of PSC in disease-relevant cells and tissues, and to identify potentially causative endogenous antigens. To this end, we will perform genetic fine mapping for the human leukocyte antigen region (HLA; chromosome 6p21), the immunoglobulin-like receptor region (KIR; 19q13. 42) and 22 previously established non-HLA susceptibility loci, using genome-wide data from a large case population totalling 3,408 PSC patients and 34,213 healthy controls, followed by HLA-KIR- and HLA/non-HLA interaction (epistasis) analyses. An analysis of newly generated whole exome sequencing (WES) data from 877 German PSC patients and 3,449 healthy controls will help identify causative genes and protein-coding risk variants within and outside known susceptibility loci. We will perform network-based in silico screenings in combination with drug databases to suggest agents that may be candidates for use in PSC. Using cross-tissue expression imputation models by modelling whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) data from blood, liver, and intestinal tissues simultaneously, we will perform transcriptome-wide association studies (TWAS) for PSC patients and controls to facilitate the determination of disease-associated genes. Peptidome-wide association studies (PepWAS), peptide binding predictions and peptide elution experiments will be performed to derive possible disease-relevant endogenous peptides and an in silico immunopeptidome for each of the 877 German PSC patients and 3,449 controls. Finally, we are preparing the results of the immunogenetic analyses in such a way that clinical researchers can perform functional follow-up experiments and develop new individual therapeutic approaches.