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- Weismuller, T. J., et al.
(författare)
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Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
- 2017
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 152:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P <.001 and HR, 0.90; P =.03, respectively) and malignancy (HR, 0.68; P =.008 and HR, 0.77; P =.004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P <.001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P =.002 and HR, 0.68; P <.001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P <.001 and adjusted HR for women, 0.48; P =.003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P <.001) or no IBD (HR, 1.15; P =.002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
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- Alberts, R, et al.
(författare)
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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:8, s. 1517-1524
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Tidskriftsartikel (refereegranskat)abstract
- 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.DesignWe 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.ResultsWe 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.ConclusionWe 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.
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- Berntsen, N. L., et al.
(författare)
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Association between HLA haplotypes and increased serum levels of IgG4 in patients with primary sclerosing cholangitis
- 2015
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 148:5
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Tidskriftsartikel (refereegranskat)abstract
- Increased serum levels of IgG4 have been reported in 9%-15% of patients with primary sclerosing cholangitis (PSC); it is not clear whether this increase contributes to pathogenesis. We performed genetic analyses of the HLA complex in patients with PSC from Norway, Sweden, and from the United States. We found an association between levels of IgG4 above the upper reference limit and specific HLA haplotypes. These patients had a significantly lower frequency of the strongest PSC risk factor, HLA-B∗08, than patients without increased IgG4, and significantly higher frequencies of HLA-B∗07 and HLA-DRB1∗15. HLA genotype therefore might affect the serum concentration of IgG4, and increased IgG4 might be a marker of a distinct phenotype of PSC. © 2015 AGA Institute.
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- Boberg, Lena, et al.
(författare)
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Signaling and metabolic properties of fast and slow smooth muscle types from mice
- 2018
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Ingår i: Pflügers Archiv. - : Springer. - 0031-6768 .- 1432-2013. ; 470:4, s. 681-691
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Tidskriftsartikel (refereegranskat)abstract
- This study aims to improve the classification of smooth muscle types to better understand their normal and pathological functional phenotypes. Four different smooth muscle tissues (aorta, muscular arteries, intestine, urinary bladder) with a 5-fold difference in maximal shortening velocity were obtained from mice and classified according to expression of the inserted myosin heavy chain (SMHC-B). Western blotting and quantitative PCR analyses were used to determine 15 metabolic and 8 cell signaling key components in each tissue. The slow muscle type (aorta) with a 12 times lower SMHC-B had 6-fold lower expression of the phosphatase subunit MYPT1, a 7-fold higher expression of Rhokinase 1, and a 3-fold higher expression of the PKC target CPI17, compared to the faster (urinary bladder) smooth muscle. The slow muscle had higher expression of components involved in glucose uptake and glycolysis (type 1 glucose transporter, 3 times; hexokinase, 13 times) and in gluconeogenesis (phosphoenolpyruvate carboxykinase, 43 times), but lower expression of the metabolic sensing AMP-activated kinase, alpha 2 isoform (5 times). The slow type also had higher expression of enzymes involved in lipid metabolism (hormone-sensitive lipase, 10 times; lipoprotein lipase, 13 times; fatty acid synthase, 6 times; type 2 acetyl-coenzyme A carboxylase, 8 times). We present a refined division of smooth muscle into muscle types based on the analysis of contractile, metabolic, and signaling components. Slow compared to fast smooth muscle has a lower expression of the deactivating phosphatase and upregulated Ca2+ sensitizing pathways and is more adapted for sustained glucose and lipid metabolism. © 2018 The Author(s)
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