Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Abstract

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10−9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Design and Endpoints for Clinical Trials in Primary Sclerosing Cholangitis

“…There are several critical challenges in the evaluation of biomarkers as “reasonably likely” surrogates in PSC: (1) basic understanding of disease pathogenesis is limited; (2) PSC disease drivers have not been identified; (3) there are no biomarkers that are specifically linked to the cause of the disease; (4) phenotypic variability results in multiple different clinical outcomes such as CCA, bacterial cholangitis, DS, IBD, CRC, etc. ; (5) liver fibrosis (LF) is not a sole determinant of outcomes, therefore a biomarker that measures fibrosis is not likely to capture the effects on the bile duct disease, on IBD, and their complications, which may impact clinically meaningful outcomes; (6) limited numbers of patients are available for big data approaches, as well as for gene and protein discovery; and (7) there are no validated genetic markers for severity of disease course, although, recently, genotype‐phenotype analysis in a large IPSCSG cohort identified R‐spondin3 (RSPO3) to be associated with TFS in PSC …”

“…; (5) liver fibrosis (LF) is not a sole determinant of outcomes, therefore a biomarker that measures fibrosis is not likely to capture the effects on the bile duct disease, on IBD, and their complications, which may impact clinically meaningful outcomes; (6) limited numbers of patients are available for big data approaches, as well as for gene and protein discovery; and (7) there are no validated genetic markers for severity of disease course, although, recently, genotype-phenotype analysis in a large IPSCSG cohort identified R-spondin3 (RSPO3) to be associated with TFS in PSC. (44) BioCHeMiCal MaRKeRs alp Patterns of ALP elevations are different than observed in PBC, in that there are patients who present with elevated ALP levels, which then normalize and these patients may have better outcome than those with persistently elevated ALP levels. This "spontaneous normalization" is rare in PBC.…”

PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC

“…Compared to other chronic liver diseases, little is known about genetic modifiers of liver injury in cholestatic conditions. Alberts et al [ 23 ] analyzed 3,402 patients with PSC who were genotyped using an “Immunochip” (variants n = 130,422). The authors identified association between rs853974 in the gene RSPO3 and transplant-fee survival, and this variant also influenced the risk of PSC-related death during the follow-up [ 23 ].…”

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

“…The pathobiologic mechanisms regulating periportal fibrogenesis and to what extent these processes contribute to the progression of disease remain poorly understood . What is becoming clear, based on genome‐wide association studies, is that genetic causes alone are not sufficient to fully explain the pathobiology . Rather, it appears that the pathogenesis of biliary fibrosis is a complex process involving factors such as specific environmental exposures in genetically susceptible individuals as well as complex interactions with the microbiome and the immune system .…”