Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597381
2. Clinical Hepatology
Georg Thieme Verlag KG Stuttgart · New York

NOD2 genetic variants confer risk for secondary sclerosing cholangitis in critically ill patients

C Jüngst
1   Saarland University Medical Center, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
V Stadlbauer-Köllner
2   Medical University of Graz, Division of Gastroenterology und Hepatology, Graz, Austria
,
M Reichert
1   Saarland University Medical Center, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
SN Weber
1   Saarland University Medical Center, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
L Ofner-Ziegenfuß
3   Medical University of Graz, Institute of Human Genetics, Graz, Austria
,
T Voigtländer
4   Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
,
W Spindelböck
2   Medical University of Graz, Division of Gastroenterology und Hepatology, Graz, Austria
,
P Fickert
2   Medical University of Graz, Division of Gastroenterology und Hepatology, Graz, Austria
,
G Kirchner
5   University of Regensburg, Department of Internal Medicine I, Regensburg, Germany
,
F Lammert
1   Saarland University Medical Center, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
TO Lankisch
4   Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
,
M Krawczyk
1   Saarland University Medical Center, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

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Introduction: Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease. Its etiology is unknown. It has been hypothesized that biliary infections might be involved in the pathogenesis. Hence in the current study we investigate if common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, which we previously identified to represent not only risk factors for Crohn's disease but also for bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP.

Patients and methods: We screened a total of 4,641 endoscopic retrograde cholangiography procedures and identify 17 patients (14 men, median age 63 years) with SC-CIP (Cohort 1, discovery cohort), who were then genotyped for the three common NOD2 mutations. To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional academic medical centers (Cohort 2, replication cohort). In addition, we genotyped specific polymorphisms of hepatocanalicular transporter genes to investigate their role in the development of SC-CIP.

Results: In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. Four patients carried the p.R702W variant and one patient harbored the c.3020insC variant. These results were replicated in Cohort 2 with 8 SC-CIP patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms in hepatocanalicular transporter genes did not have major impact on SC-CIP risk.

Conclusion: This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation. These results suggest a pivotal role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.