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

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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.