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Dive into the research topics where Christian Rupp is active.

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Featured researches published by Christian Rupp.


Hepatology | 2013

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4

David Ellinghaus; Trine Folseraas; Kristian Holm; Eva Ellinghaus; Espen Melum; Tobias Balschun; Jon K. Laerdahl; Alexey Shiryaev; Daniel Gotthardt; Tobias J. Weismüller; Christoph Schramm; Michael Wittig; Annika Bergquist; Einar Björnsson; Hanns-Ulrich Marschall; Morten H. Vatn; Andreas Teufel; Christian Rust; Christian Gieger; H-Erich Wichmann; Heiko Runz; Martina Sterneck; Christian Rupp; Felix Braun; Rinse K. Weersma; Cisca Wijmenga; Cyriel Y. Ponsioen; Christopher G. Mathew; Paul Rutgeerts; Severine Vermeire

Approximately 60%‐80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome‐wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune‐mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome‐wide significant associations with PSC at 2q37 [rs3749171 at G‐protein‐coupled receptor 35 (GPR35); P = 3.0 × 10−9 in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24‐1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10−8, OR (95% CI) = 0.75 (0.68‐0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome‐wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2013;58:1074–1083)


Alimentary Pharmacology & Therapeutics | 2014

Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis

Christian Rupp; A. Rössler; E. Halibasic; Peter Sauer; Kh Weiss; Kilian Friedrich; Andreas Wannhoff; Adolf Stiehl; Wolfgang Stremmel; Michael Trauner; Daniel Gotthardt

Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype.


Journal of Hepatology | 2013

FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.

Andreas Wannhoff; Johannes R. Hov; Trine Folseraas; Christian Rupp; Kilian Friedrich; Jarl Andreas Anmarkrud; Karl Heinz Weiss; Peter Sauer; Peter Schirmacher; Kirsten Muri Boberg; Wolfgang Stremmel; Tom H. Karlsen; Daniel Gotthardt

BACKGROUND & AIMS Allelic variants of fucosyltransferases 2 and 3 (FUT2/3) influence serum levels of CA19-9, a screening parameter commonly used for detection of biliary malignancy in PSC. We aimed at improving diagnostic accuracy of CA19-9 by determining the impact of FUT2/3 genotypes. METHODS CA19-9 levels were measured in 433 PSC patients, 41 of whom had biliary malignancy. Genotypes for FUT3 and FUT2 were used to assign patients to one of three groups: A, no FUT3 activity regardless of FUT2 activity; B, both FUT2 and FUT3 activity and C, no FUT2 activity without loss of FUT3 activity. Group-specific cut-off values were determined by Youdens index. RESULTS The median CA19-9 values of cancer-free patients were significantly different (p<0.001) in Groups A (2.0U/ml), B (17.0U/ml), and C (37.0U/ml). Biliary malignancy patients in Groups B and C had significantly higher CA19-9 values than cancer-free patients (p<0.001). The optimal cut-off, as determined by ROC analysis, for all patients was 88.5U/ml. Optimal cut-off values in Groups A, B, and C were 4.0U/ml, 74.5U/ml, and 106.8U/ml, respectively. Use of these values improved sensitivity of CA19-9 in Groups B and C. Further, use of group-dependent cut-off values with 90% sensitivity resulted in a 42.9% reduction of false positive results. CONCLUSIONS Use of FUT2/3 genotype-dependent cut-off values for CA19-9 improved sensitivity and reduced the number of false positive results.


Liver Transplantation | 2016

Biliary Strictures and Recurrence After Liver Transplantation for Primary Sclerosing Cholangitis: A Retrospective Multicenter Analysis

Tatiana Hildebrand; Nadine Pannicke; Alexander Dechêne; Daniel Gotthardt; Gabriele I. Kirchner; Fp Reiter; Martina Sterneck; Kerstin Herzer; Henrike Lenzen; Christian Rupp; Hannelore Barg-Hock; Philipp de Leuw; Andreas Teufel; Vincent Zimmer; Frank Lammert; Christoph Sarrazin; Ulrich Spengler; Christian Rust; Michael P. Manns; Christian P. Strassburg; Christoph Schramm; Tobias J. Weismüller

Liver transplantation (LT) is the only definitive treatment for patients with end‐stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow‐up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow‐up for 98.8 months. The 1‐, 5‐, and 10‐year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient‐donor constellation. Liver Transpl 22:42‐52, 2016.


Endoscopy | 2013

Bacteriobilia and fungibilia are associated with outcome in patients with endoscopic treatment of biliary complications after liver transplantation.

Daniel Gotthardt; Karl Heinz Weiss; Christian Rupp; Konrad A. Bode; Isabella Eckerle; Gerda Rudolph; Janine Bergemann; Petra Kloeters-Plachky; Fadi Chahoud; Markus W. Büchler; Peter Schemmer; Wolfgang Stremmel; Peter Sauer

BACKGROUND AND STUDY AIMS To determine the importance of bacteriobilia and fungibilia in patients with endoscopic treatment of biliary complications after orthotopic liver transplantation (OLT). PATIENTS AND METHODS In a prospective study at a tertiary center, 213 patients underwent 857 endoscopic retrograde cholangiographies (ERCs) after OLT. Findings at first ERC were: anastomotic stricture in 24.4%, nonanastomotic stricture in 18.3%, leakage in 11.3%, and gallstones in 4.7%. RESULTS Bile samples from first ERC showed Gram-positive bacterial isolates in 102/180 (57%) and Gram-negative in 44/180 (24%). Main species were Enterococcus spp. (40%; 72/180) and Escherichia coli (10%; 18 /180). Enteric bacteria (present in 47%) and Candida spp. (present in 18%) were both associated with clinical signs of cholangitis, but not with laboratory signs of inflammation. Multiresistant strains (present in 12% of samples) showed no association with clinical or laboratory parameters. Detection of microbiological isolates was independent of endoscopic findings and treatment. In patients with successful endoscopic intervention, the actuarial survival free of retransplantation was significantly lower in those with detection of enteric bacteria, being 51.8 months (95% confidence interval [CI] 42.9-60.6) vs. 62.9 months (95% CI 59.1-66.7); P = 0.025). Fungibilia was associated with significantly lower actuarial retransplantation-free survival, independently of successful endoscopic treatment (mean 35.1 months [95% CI 23.5-46.7] vs. 53.1 months [(95% CI 48.0-58.2]; P = 0.019). CONCLUSIONS Bacteriobilia and fungibilia can frequently be detected by routine microbiological sampling in patients after OLT. Regular bile sampling is recommended since the presence of difficult-to-treat multiresistant strains is unpredictable. Survival is affected by this altered biliary microbiological environment after OLT.


PLOS ONE | 2013

A Frequent PNPLA3 Variant Is a Sex Specific Disease Modifier in PSC Patients with Bile Duct Stenosis

Kilian Friedrich; Christian Rupp; Johannes R. Hov; Niels Steinebrunner; Kh Weiss; Adolf Stiehl; Maik Brune; Petra Schaefer; Peter Schemmer; Peter Sauer; Peter Schirmacher; Heiko Runz; Tom H. Karlsen; Wolfgang Stremmel; Daniel Gotthardt

Background & Aims Primary sclerosing cholangitis predominantly affects males and is an important indication for liver transplantation. The rs738409 variant (I148M) of the PNPLA3 gene is associated with alcoholic and non-alcoholic liver disease and we evaluated its impact on the disease course of PSC. Methods The I148M polymorphism was genotyped in 121 German PSC patients of a long-term prospective cohort and 347 Norwegian PSC patients. Results In the prospective German cohort, actuarial survival free of liver transplantation was significantly reduced for I148M carriers (p = 0.011) compared to wildtype patients. This effect was restricted to patients with severe disease, as defined by development of dominant stenosis (DS) requiring endoscopic intervention. DS patients showed markedly decreased survival (p = 0.004) when carrying the I148M variant (I148M: mean 13.8 years; 95% confidence interval: 11.6–16.0 vs. wildtype: mean 18.6 years; 95% confidence interval: 16.3–20.9) while there was no impact on survival in patients without a DS (p = 0.87). In line with previous observations of sex specific effects of the I148M polymorphism, the effect on survival was further restricted to male patients (mean survival 11.9 years; 95% confidence interval: 10.0–14.0 in I148M carriers vs. 18.8 years; 95% confidence interval: 16.2–21.5 in wildtype; p<0.001) while female patients were unaffected by the polymorphism (p = 0.65). These sex specific findings were validated in the Norwegian cohort (p = 0.013). Conclusions In male PSC patients with severe disease with bile duct stenosis requiring intervention, the common I148M variant of the PNPLA3 gene is a risk factor for reduced survival.


Alimentary Pharmacology & Therapeutics | 2014

Fut2 genotype is a risk factor for dominant stenosis and biliary candida infections in primary sclerosing cholangitis

Christian Rupp; Kilian Friedrich; Trine Folseraas; Andreas Wannhoff; Konrad A. Bode; Kh Weiss; P. Schirmacher; Peter Sauer; Wolfgang Stremmel; Daniel Gotthardt

A recent genome‐wide association study identified the FUT2 secretor status and genotype defined by the single‐nucleotide polymorphism rs601338 as potential genetic risk factor in primary sclerosing cholangitis (PSC), which significantly influences biliary bacterial composition.


PLOS ONE | 2012

S100A9 is a biliary protein marker of disease activity in primary sclerosing cholangitis.

Lisa Reinhard; Christian Rupp; Hans-Dieter Riedel; Thomas Ruppert; Thomas Giese; Christa Flechtenmacher; Karl Heinz Weiss; Petra Kloeters-Plachky; Wolfgang Stremmel; Peter Schirmacher; Peter Sauer; Daniel Gotthardt

Background and Aims Bile analysis has the potential to serve as a surrogate marker for inflammatory and neoplastic disorders of the biliary epithelium and may provide insight into biliary pathophysiology and possible diagnostic markers. We aimed to identify biliary protein markers of patients with primary sclerosing cholangitis (PSC) by a proteomic approach. Methods Bile duct-derived bile samples were collected from PSC patients (n = 45) or patients with choledocholithiasis (n = 24, the control group). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to analyse the proteins, 2-D-gel patterns were compared by densitometry, and brush cytology specimens were analysed by RT-PCR. Results A reference bile-duct bile proteome was established in the control group without signs of inflammation or maligancy comprising a total of 379 non-redundant biliary proteins; 21% were of unknown function and 24% had been previously described in serum. In PSC patients, the biliary S100A9 expression was elevated 95-fold (p<0.005), serum protein expression was decreased, and pancreatic enzyme expression was unchanged compared to controls. The S100A9 expression was 2-fold higher in PSC patients with high disease activity than in those with low activity (p<0.05). The brush cytology specimens from the PSC patients with high disease activity showed marked inflammatory activity and leukocyte infiltration compared to the patients with low activity, which correlated with S100A9 mRNA expression (p<0.05). Conclusions The bile-duct bile proteome is complex and its analysis might enhance the understanding of cholestatic liver disease. Biliary S100A9 levels may be a useful marker for PSC activity, and its implication in inflammation and carcinogenesis warrants further investigation.


Liver International | 2013

Non‐IBD immunological diseases are a risk factor for reduced survival in PSC

Christian Rupp; Anne Mummelthei; Peter Sauer; Karl Heinz Weiss; Peter Schirmacher; Adolf Stiehl; Wolfgang Stremmel; Daniel Gotthardt

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. It is known to be associated with immunological diseases (IDs), such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH).


BMC Infectious Diseases | 2014

Risk factors and outcome in patients with primary sclerosing cholangitis with persistent biliary candidiasis

Christian Rupp; Konrad A. Bode; Fadi Chahoud; Andreas Wannhoff; Kilian Friedrich; Kh Weiss; Peter Sauer; Wolfgang Stremmel; Daniel Gotthardt

BackgroundCandidiasis is commonly observed in patients with primary sclerosing cholangitis (PSC), but the clinical risk factors associated with its presence have not been fully investigated. In this study, we aimed to analyse the incidence, risk factors, and transplantation-free survival in primary sclerosing cholangitis (PSC) patients with persistent biliary candidiasis.MethodsWe retrospectively analysed patients diagnosed with PSC who were admitted to our department during 2002 to 2012. One-hundred fifty patients whose bile cultures were tested for fungal species were selected, and their clinical and laboratory parameters were investigated. The results of endoscopic retrograde cholangiography (ERC) and bile cultures were analysed using chart reviews. The cases of biliary candidiasis were sub-classified as transient or persistent.ResultsThirty out of 150 (20.0%) patients had biliary candidiasis. Although all patients demonstrated comparable baseline characteristics, those with biliary candidiasis showed significantly reduced transplantation-free survival (p < 0.0001) along with a markedly elevated frequency of cholangiocarcinoma (CCA) (p = 0.04). The patients were further sub-classified according to the transient (15/30) or persistent (15/30) nature of their biliary candidiasis. A subgroup analysis showed reduced survival with a greater necessity for orthotopic liver transplantation (OLT) only in patients with persistence of Candida (p = 0.007). The survival in the patients with transient biliary candidiasis was comparable to that in candidiasis-free patients. In a multivariate regression analysis that included Mayo risk score (MRS), sex, age, dominant stenosis, inflammatory bowel disease, autoimmune hepatitis overlap syndrome, and number of times ERC was performed, biliary candidiasis was an independent risk factor for reduced survival (p = 0.008). Risk factors associated with acquisition of biliary candidiasis were age at PSC diagnosis and number of ERCs.ConclusionsThe persistence of biliary candidiasis is associated with markedly reduced transplantation-free survival in PSC patients. By contrast, actuarial survival in patients with transient biliary candidiasis approaches that for patients without any evidence of biliary candidiasis. Further studies on the treatment of persistent biliary candidiasis in patients with PSC are warranted.

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Daniel Gotthardt

University Hospital Heidelberg

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Kh Weiss

University Hospital Heidelberg

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Kilian Friedrich

University Hospital Heidelberg

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Wolfgang Stremmel

University Hospital Heidelberg

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Karl Heinz Weiss

University Hospital Heidelberg

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Peter Schirmacher

University Hospital Heidelberg

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Andreas Wannhoff

University Hospital Heidelberg

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