Making steps in discovering the pathogenesis of Primary Sclerosing Cholangitis: a cohort description and a genetic investigation

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic disorder of the bile ducts. In up to 80% of all PSC patients, also inflammatory bowel disease (IBD) is present. Shared common pathways are suggested for PSC and IBD. Currently no effective medical treatment is available for PSC, which is due to the largely unknown pathogenesis. Few cohort descriptions exist that present clinical outcomes. Furthermore genetic research was done and currently four non-HLA loci are known to be associated with PSC, two of them are also ulcerative colitis (UC) risk loci. In this study on the one hand a Dutch PSC cohort was described to add clinical information about PSC, on the other hand 13 markers for UC risk loci were genotyped in PSC patients to identify more PSC risk loci and thereby replenish our knowledge about the pathogenesis. MATERIAL AND METHODS: A retrospective cohort review was performed on all known PSC patients in the University Medical Center Groningen. Clinical data were collected in a database by reviewing all PSC patient files. In the genetic part of the study 835 PSC patients and 1481 controls from the Benelux, Germany and Scandinavia were genotyped for 13 single nucleotide polymorphisms (SNP’s). These SNP’s were markers for novel UC risk loci (FCGR2, PUS10/REL, IL2/IL21, Cep72, SMURF1-KPNA7, LAMB1, JAK2, CARD9, CIITA, CDH1, ORMDL3, HNF4A and IL17REL). Allelic association analyses were performed between cases and controls. Subsequently an analysis was done for PSC cases with and without IBD separately to define specific PSC associated loci. RESULTS: The retrospective cohort description was done for 241 Dutch PSC patients from the UMCG. PSC patients frequently (24,9%) had concomitant other immune mediated diseases like auto immune hepatitis, sarcoidosis, thyroid disease or psoriasis. Time to transplantation was influenced by IBD status and the presence of symptoms at presentation of PSC. Furthermore age at diagnosis in our cohort was younger than in other cohorts and it seemed to be influenced by IBD status. By genotyping 13 UC risk loci in PSC, three loci were found to be significantly associated: IL2/IL21 (0,0002), PUS10/REL (0,0023) and CARD9 (0,0035). HNF4A showed a trend towards significance (0,047). After analyzing IBD phenotypes the CARD9 gene was moderately associated in PSC patients without IBD. CONCLUSION: The retrospective cohort description is a useful supplement to existing literature, as we analyzed a Dutch PSC cohort from a tertiary referral center and we discovered a high amount of patients having other immune related diseases besides PSC and IBD, which was never described before. Also we identified two influencing factors for time to transplantation and one for age at diagnosis of PSC. In the genetic part of this study we discovered three new PSC loci: IL2/IL21, PUS10/REL and CARD9. For these loci trends towards significance were also identified in patients without IBD. As all loci are involved in the immune system, PSC seems to be at least partly immune mediated.