Citations 3
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
Alberts, Rudi , Vries, Elisabeth M. G. de, Goode, Elizabeth C. , Jiang, Xiaojun , Sampaziotis, Fotis , Rombouts, Krista , Böttcher, Katrin , Folseraas, Trine , Weismüller, Tobias J. , Alexander, Graeme, Alvaro, Domenico , Bergquist, Annika , Björkström, Niklas K. , Beuers, Ulrich , Boberg, Kirsten Muri , Bowlus, Christopher L. , Bragazzi, Maria Consiglia , Chazouillères, Olivier , Cheung, Angela , Dalekos, Georgios, Eaton, John E. , Eksteen, Bertus , Ellinghaus, David , Färkkilâ, Martti , Festen, Eleonora A. , Floreani, Annarosa , Franceschet, I., Gotthardt, Daniel , Hoek, Bart van , Holm, Kristian , Hov, Johannes R. , Imhann, Floris , Juran, Brian D., Lenzen, Henrike , Marschall, Hanns–Ulrich , Marzioni, Marco , Melum, Espen , Milkiewicz, Piotr , Müller, Tobias , Parés, Albert , Rupp, Christian , Rust, Christian, Sandford, Richard , Schrumpf, Erik, Silverberg, Mark S. , Srivastava, Brijesh, Sterneck, Martina , Teufel, Andreas , Vallier, Ludovic , Verheij, Joanne , Vila, Arnau Vich , Vries, Boudewijn de, Zachou, Kalliopi , Chapman, Roger W. , Manns, Michael P. , Rushbrook, Simon, Anderson, Carl A. , Karlsen, Tom H. , Ponsioen, Cyriel Y. , Weersma, Rinse K. , Eaton, John, Lazaridis, Konstantinos N. , Ellinghaus, David , Bowlus, Christopher L , Marzioni, Marco , Mason, Andrew L. , Wang, Weiwei , Bjornsson, Einar Stefan , Carbone, Marco , Dalekos, Georgios, Hirschfield, Gideon M. , Hohenester, Simon D. , Invernizzi, Pietro , Lieb, Wolfgang , Liu, Jimmy Z. , Schramm, Christoph , Schreiber, Stefan , Pinzani, Massimo , Franke, André , Bergquist, Annika , Milkiewicz, Piotr , Alvaro, Domenico , Hov, Johannes R , Anderson, Carl A
Gut | August 4, 2017 | Volume: 67 | Issue: 8 | Pages: 1517-1524
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.
HLA haplotypes in primary sclerosing cholangitis patients of admixed and non‐European ancestry
Henriksen, Eva , Viken, Marte K. , Wittig, Michael , Holm, Kristian , Folseraas, Trine , Mucha, Sören , Melum, Espen , Hov, Johannes R. , Lazaridis, K.N., Juran, Brian D., Chazouillères, O., Färkkilâ, Martti , Gotthardt, Daniel , Carbone, Marco , Hirschfield, Gideon M. , Rushbrook, Simon, Goode, Elizabeth C. , Ponsioen, Cyriel Y. , Weersma, Rinse K. , Eksteen, Bertus , Yimam, Kidist, Goldberg, David S. , Yu, Leonard T., Bowlus, Christopher L. , Lie, Benedicte A. , Karlsen, Tom H. , Henriksen, E K K , Viken, M K , Invernizzi, Pietro , Gordon, Stuart C. , Franke, André , Bowlus, Christopher L , Carbone, Marco , Hirschfield, Gideon M , Hov, Johannes R
HLA | July 11, 2017 | Volume: 90 | Issue: 4 | Pages: 228-233
Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non‐European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA‐DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA‐DQB1*06:03. In contrast, only 65% of HLA‐DRB1*13:01 haplotypes in an admixed/non‐European PSC population carried this allele, suggesting that further assessments of the PSC‐associated haplotype HLA‐DRB1*13:01‐DQA1*01:03‐DQB1*06:03 in admixed or multi‐ethnic populations could aid in identifying the causative allele.
Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease
Næss, Sigrid, Anmarkrud, Jarl Andreas , Mamari, Said Al, Juran, Brian D., Chapman, Roger W. , Bergquist, Annika , Melum, Espen , Schrumpf, Erik, Lie, Benedicte A. , Boberg, Kirsten Muri , Karlsen, Tom H. , Hov, Johannes R. , Bjornsson, Einar Stefan , Lazaridis, Konstantinos N. , Marsh, Steven G. E. , Bergquist, Annika , Hov, Johannes R
Liver International | February 12, 2014 | Volume: 34 | Issue: 10 | Pages: 1488-1495
AbstractBackground & AimsSmall duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC.MethodsFour classical HLA loci (HLA‐A, HLA‐B, HLA‐C and HLA‐DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions.ResultsHLA‐DRB1*13:01 (OR = 2.0, 95% CI 1.2–3.4, P = 0.01) and HLA‐B*08 (OR = 1.6, 95% CI 1.1–2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA‐B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4–65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA‐DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC.ConclusionsSmall duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA‐DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.