Increased prevalence of low-frequency- and rare NOD2 variants in patients with cirrhosis treated in tertiary care hepatology centers

Background and aims:

In the last years, genome-wide association (GWAS) studies have robustly identified common genetic risk variants for cirrhosis of various etiologies (Karlsen & Lammert J Hep 2015). This do not fully explain heritability, since low frequency and rare variants are missed by GWAS (Auer et al. Genome Med 2015). Here we explored the association of common low-frequency and rare variants in the Nucleotide-binding oligomerisation domain containing 2 (NOD2) gene with cirrhosis, investigating three known risk variants and two recently single nucleotide polymorphisms (SNPs) identified in high-resolution mapping (Huang et al. Nature 2017) in patients being screening for the INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites, EudraCT 2013 – 001626 – 26).

Patients and methods:

In the participating 17 tertiary care hepatology referral centers throughout Germany, potential study participants were genotyped for the three NOD2 variants (p.R702W, p.G908R and c.3020insC) and the two novel variants p.N289S and rs72796367 (intronic) using PCR-based allelic discrimination assays with 5'-nuclease and fluorescence detection. Prevalence rates and allelic frequencies of the NOD2 variants were calculated.

Results:

Overall, 2605 patients have been genotyped for the three known and the two recently described NOD2 variants (p.N289S and rs72796367). In the screening cohort, the most common risk variant was p.R702W (allele frequency 5.9%, 318 patients), followed by c.3020insC (3.5%, 184 patients) and p.G908R (1.8%, 94 patients). The allele frequencies of the rare variants were 2.9% (rs72796367, 152 patients) and 0.9% (p.N289S, 48 patients). Within a subgroup of patients recruited in Homburg and Halle (n = 750), the prevalence of these variants did not differ when stratified for Child-Pugh classes A-C, compensated/decompensated cirrhosis or liver stiffness (elastography). According to available data in healthy adults, the NOD2 variant allele frequencies in the ExAC (non-Finnish Europeans) and dbSNP databases are 3.5% (p.R702W), 2.0% (c.3020insC), 1.5% (p.G908R), 0.7% (rs72796367) and 0.6% (p.N289S).

Conclusions:

In our patients with liver cirrhosis genotyped in tertiary care hepatology centers, the prevalence of the three common NOD2 risk variants as well as p.N289S is about twice as high as the frequency in the general population, and about four times higher for variant rs72796367. Investigation of the mechanisms of this association, including pathological bacterial translocation and alteration of gut microbiota, is warranted.

 

MissingLinkText