Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597410
2. Clinical Hepatology
Georg Thieme Verlag KG Stuttgart · New York

Screening for the INCA trial: Increased prevalence of common NOD2 risk variants in patients with cirrhosis in tertiary liver centers

M Reichert
1   Saarland University Medical Center, Department of Medicine II, Homburg, Germany
,
M Casper
1   Saarland University Medical Center, Department of Medicine II, Homburg, Germany
,
B Appenrodt
1   Saarland University Medical Center, Department of Medicine II, Homburg, Germany
,
F Grünhage
1   Saarland University Medical Center, Department of Medicine II, Homburg, Germany
,
F Lammert
1   Saarland University Medical Center, Department of Medicine II, Homburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

 

Background and Aim: Patients with liver cirrhosis display an increased risk of bacterial infections that decrease survival rates. Nucleotide-binding oligomerisation domain containing 2 (NOD2) germline variants were found to be associated with spontaneous bacterial peritonitis and mortality in patients with cirrhosis (Appenrodt et al. 2010). The INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites, EudraCT 2013 – 001626 – 26) trial investigates in a randomized double-blind, placebo-controlled design (norfloxacin 400 mg once daily vs. placebo) whether survival of a genetically defined high-risk group of patients with cirrhosis carrying NOD2 variants is improved by primary antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. As the overall prevalence of NOD2 variants in patients with liver cirrhosis is unknown, our aim now was to analyze the prevalence of the NOD2 variants in patients being evaluated or screened for the INCA trial.

Patients and methods: Patients for this national multicenter study are recruited in 17 centers throughout Germany. In the participating tertiary care liver centers, potential study participants are genotyped for the three common NOD2 variants (p.R702W, p.G908R and c. 3020insC) using a PCR-based assay with 5'-nuclease and fluorescence detection. We determined allele and genotype distributions for the NOD2 variants across the INCA study centers.

Results: Overall, 1,646 patients have been genotyped for the three common NOD2 risk variants since February 2014. The frequency of any NOD2 risk variant was 22.3% (367/1646) for all centers, and for centers screening a minimum of 20 patients, the mean prevalence was 21.0% (SEM ± 1.2%, range 15 – 29%). More than 30 patients were screened in Homburg (732), Bonn (103), Frankfurt (100), Hamburg (74), Jena (39), Kaiserslautern (76), Leipzig (35), Mainz (31), Heidelberg (47), Mannheim (137) and Halle (220). The most common risk variant was p.R702W (13.1%, 215 patients), followed by c. 3020insC (7.9%, 130 patients) and p.G908R (3.5%, 58 patients). Nineteen patients (1.2%) carried two risk variants. According to available data in healthy adults, the NOD2 variant allele frequencies in the ExAC browser (Europeans) are 3.5% (p.R702W), 2.0% (c. 3020insC), 1.5% (p.G908R), and combined 7.0%; in another cohort including healthy Caucasians, the prevalence rates were 4.3% (p.R702W), 2.3% (c. 3020insC), 1.2% (p.G908R), and combined 7.8% (Hugot et al. 2007).

Conclusions: In our patients genotyped in tertiary care liver centers, the prevalence of NOD2 risk variants is about three times the frequency compared to the healthy population, with similar distribution of the three single variants. Investigation of the association of NOD2 risk variants with clinical endpoints is warranted.