Effects of SNPs in HE-relevant genes on the development of hepatic encephalopathy in patients with liver cirrhosis

Background:

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that emerges in acute and chronic liver failure. Currently, HE is seen as a clinical manifestation of a low grade cerebral edema and cerebral oxidative stress which disturbs oscillatory networks and synaptic plasticity in brain. Importantly, HE is a negative prognostic risk factor in liver cirrhosis for higher mortality.

Aims and Methods:

The current study was undertaken to identify genetic risk factors that may determine the development of a hepatic encephalopathy. For this a Next Generation Sequencing (NGS) chip was developed, representing the whole coding region including selected promoter regions in 7 genes potentially being involved in the pathogenesis of hepatic encephalopathy.

DNA samples were collected from 33 patients with liver cirrhosis and an episode of hepatic encephalopathy, 17 patients with liver cirrhosis who never had an episode of HE so far and 17 controls, who did not have a liver cirrhosis. In addition DNA samples were collected from frozen brain tissue from donors of the body donor program of the University of Düsseldorf (6 patients with cirrhosis and HE, 6 controls without liver cirrhosis).

Results:

The current analysis identified 35 SNPs which were not specific for patients with liver cirrhosis and hepatic encephalopathy and were also found in controls and patients with liver cirrhosis without an episode of HE.

Of particular interest, the allele frequency of two SNPs of the glutamate transporter 1 (GLT-1) as well as of 5 SNPs of the solute carrier 1A5 (SLC1A5) was either higher (rs1060043, rs2070246, rs313853) or lower (rs752949, rs3027958, rs1042113, rs3027961) in the group of patients with liver cirrhosis and HE compared to our control group of patients without liver cirrhosis and an additional control group from the database gnomAD, without reaching statistical significance yet (p < 0.05). Interestingly, the frequency of a homocygote occurance of these SNPs was as well remarkably higher or lower in the group of patients with HE compared to the control groups, respectively.

The allele frequency of two of the SNPs of SLC1A5 (rs1060043, rs2070246) was significantly higher in the group of patients with liver cirrhosis and HE compared to the group of patients with liver cirrhosis without HE.

Discussion:

Our study suggests that SNPs may play a role for the pathogenesis of HE. However, further research is needed to validate the present findings and to identify consequences of the individual SNPs for the respective protein function.