Exome Sequencing Study Uncovers Rare Variants in Gene Protecting Against Liver Disease

Rare germline mutations in the CIDEB gene provide protection against developing liver disease and point toward a possible treatment for conditions like nonalcoholic steatohepatitis (NASH), a new Regeneron Pharmaceuticals-funded study has found.

NASH, a more severe form of nonalcoholic fatty liver disease, can lead to cirrhosis and liver failure and is becoming a leading cause of liver transplants. To uncover rare genetic variants that affect liver disease, the Regeneron team conducted a multistage exome sequencing and genetic association analysis using data from multiple large cohorts. As they reported on Wednesday in the New England Journal of Medicine, the researchers uncovered rare coding variants that influence levels of biomarkers of liver injury — including variants in CIDEB that decreased aminotransferase levels.

"The unprecedented protective effect that these CIDEB genetic variants have against liver disease provides us with one of our most exciting targets and potential therapeutic approaches for a notoriously hard-to-treat disease where there are currently no approved treatments," Aris Baras, senior VP and head of the Regeneron Genetics Center, said in a statement.

In the first stage of the study, the researchers conducted an analysis of gene-burden associations with alanine aminotransferase levels using data on 542,904 individuals from the UK Biobank and the Geisinger Health System MyCode cohort. This identified 20 associated genes, 13 of which the researchers confirmed in the second stage of the study, which examined levels of another enzyme, aspartate aminotransferase, in 540,250 individuals. These effects, the researchers noted, were independent of alanine aminotransferase-linked common genetic variants.

They further homed in on a set of five genes in which rare variants were linked to aspartate aminotransferase levels in a cohort of 24,944 individuals with liver disease and 490,636 controls. This stage included participants from the Malmö Diet and Cancer Study, the Penn Medicine BioBank, and the Mount Sinai BioMe BioBank.

Rare variants in four of these genes — APOB, ABCB4, SLC30A10, and TM6 — were linked to higher aminotransferase levels and higher risk of liver disease. But rare variants in CIDEB, which encodes a structural protein that is located on the surface of lipid droplets in hepatocytes, were associated with lower aminotransferase levels and a decreased disease risk.

People with both a predicted loss-of-function variant and a missense variant in CIDEB — about 0.7 percent of their cohort — had lower alanine aminotransferase levels and 33 percent lower odds of developing any liver disease.

Meanwhile, people who harbored one rare CIDEB variant had 53 percent lower odds of nonalcoholic liver disease and 54 percent lower odds of nonalcoholic liver cirrhosis. The mutations also conferred higher protection for individuals with obesity or type 2 diabetes, who otherwise would be at greater risk of NASH.

Using human liver cell lines, the researchers examined the effect of silencing CIDEB, both with and without added oleic acid, which is used to induce steatosis in vitro. They found that when oleic acid is added to cell lines where CIDEB is silenced, the size of lipid droplets — where CIDEB proteins typically localize — decreases. This finding suggested that CIDEB mediates the buildup of enlarged hepatic lipid droplets, which contribute to the development of liver disease.

It further suggested that inhibiting CIDEB could represent a treatment for liver disease, including NASH.

Regeneron said that it has already launched a program to target CIDEB with its collaborator Alnylam Pharmaceuticals' RNAi technology. The partners are also pursuing gene silencing treatments for NASH aimed at PNPLA3 and HSD17B13, which they also identified through human genetic studies.