Researchers from the Regeneron Genetics Center® (RGC) say they were able to uncover rare genetic loss-of-function mutations in the CIDEB gene that are associated with substantial protection from liver disease, including serious diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Their study “Germline Mutations in CIDEB and Protection against Liver Disease” appears in The New England Journal of Medicine.

“Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets,” the investigators wrote.

“We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.

“The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect.

Liver Cirrhosis, illustration
Cirrhosis is a consequence of chronic liver disease characterized by fibrosis and scarring of tissue (computer illustration). [Kateryna Kon/Science Photo Library/Getty Images]
“The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P=4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10-7).

“Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3,599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets.

“[We conclude that] rare germline mutations in CIDEB conferred substantial protection from liver disease.”

“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,” said Aris Baras, MD, senior vice president and head of the RGC at Regeneron. “RGC has repeatedly demonstrated the value of large-scale genetic sequencing in identifying novel and important targets for many serious diseases and this is yet another example of how we are fueling our pipeline through genetics discovery. Our growing dataset enables us to discover more rare and more powerful protective variants with the ultimate goal of improving human health.”

In the largest sequencing study to date on the genetic basis of liver health, RGC sequenced the exomes of more than 540,000 individuals across five ancestry groups and multiple cohorts, including the UK Biobank and the Geisinger Health System MyCode cohort. By analyzing this genetic data in conjunction with deidentified health records, RGC researchers found that individuals who carry loss-of-function mutations in one of two copies of the CIDEB gene had an approximately 53% reduction in the risk of nonalcoholic liver disease and approximately 54% reduction in the risk of nonalcoholic cirrhosis.

Individuals with obesity or type 2 diabetes also were protected

The study also found that CIDEB mutations had greater protective associations in individuals with obesity or type 2 diabetes, who are traditionally at higher risk for NASH, compared to individuals without these conditions.

Therapeutics that effectively mimic these protective mutations by blocking CIDEB expression or function could, therefore, potentially help prevent or treat NASH and other forms of liver disease, according to the scientists. Based on these findings, Regeneron has already initiated a new therapeutic program to target CIDEB working with Alnylam Pharmaceuticals’ RNA interference technology which can effectively silence genes in the liver.

Regeneron and Alnylam already have two other investigational gene silencing treatments for NASH identified via human genetics, targeting the PNPLA3 and the HSD17B13 genes. The HSD17B13 program, which is in early-phase human clinical trials, was initiated based on a previous RGC discovery of protective associations for mutations in the HSD17B13 gene.

“By catalyzing multiple therapeutic development programs targeting distinct genetic mechanisms of liver disease, the RGC’s insights are helping Regeneron develop a diversified slate of genetically-validated targets for NASH, including HSD17B13, PNPLA3, and now CIDEB,” said Luca A. Lotta, MD, PhD, vice president and head of cardiometabolic and musculoskeletal disease genetics at Regeneron.

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