Rare germline mutations in CIDEB gene protect against liver disease, damage
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In one of the largest exome-sequencing studies on liver health, researchers found rare genetic loss-of-function variants in the CIDEB gene were associated with significant protection from liver damage and disease.
The discovery, recently published in The New England Journal of Medicine, is “a milestone in our understanding of the genetic basis of nonalcoholic steatohepatitis,” Luca A. Lotta, MD, PhD, vice president and head of cardiometabolic and musculoskeletal disease genetics at Regeneron and study co-author, told Healio.
“In this study, one in every 700 individuals who carried mutations disrupting one of two copies of the CIDEB gene had about a 53% reduction in risk of nonalcoholic liver disease, about a 54% reduction in risk of nonalcoholic cirrhosis and 50% lower risk of any-cause cirrhosis,” he said. “This massive new study demonstrates that CIDEB plays a key role in NASH and that its inhibition may help prevent or treat NASH and other forms of liver disease.”
To identify genes in which rare protein-coding genetic variants were linked to liver phenotypes, researchers from the Regeneron Genetics Center (RGC) and collaborators sequenced the exomes of 542,904 individuals with data on liver aminotransferase levels. Of those, 490,636 did not have liver disease and 24,944 had varying forms of liver disease. The study included individuals of European, South Asian, African, East Asian and American ancestries and from U.K. Biobank and Geisinger Health System MyCode cohorts.
Using a multistage analysis, investigators found rare coding variants in APOB, ABCB4, SLC30A10 and TM6SF2 were linked with a higher risk for elevated aminotransferase levels and liver disease, while variants in CIDEB had a protective effect. Specifically, individuals carrying rare coding CIDEB variants had 31% to 54% lower odds for liver disease of varying causes and degrees of severity than noncarriers. The odds for any-cause cirrhosis were 50% lower.
In addition, an analysis of 3,599 patients who had bariatric surgery revealed that mutations in CIDEB were linked with decreased nonalcoholic fatty liver disease activity score at biopsy.
“To investigate the possible mechanism of the protective CIDEB mutations, RGC silenced the CIDEB gene in human cells to mimic the mutations and found that this prevented fat buildup in liver cells and resulted in smaller lipid droplets, structures that help store fat within liver cells,” Lotta said. “CIDEB belongs to a family of proteins that help build up fat within cells, and we think that the mutations we identified may block that mechanism, preventing fat buildup in the liver and the inflammation that derives from excess liver fat.”
According to Lotta, Regeneron and its partner Alnylam Pharmaceuticals are currently developing small interfering RNA therapeutics to inhibit CIDEB for the treatment of NASH and other forms of liver disease.
“With these discoveries, our main focus is on further enabling and accelerating the development of these new therapeutics with human genetics insights,” he said.
Reference:
- Regeneron Genetics Center discovers rare mutations in the CIDEB gene that protect against liver disease. https://investor.regeneron.com/news-releases/news-release-details/regeneron-genetics-center-discovers-rare-mutations-cideb-gene. Published July 27, 2022. Accessed Aug. 4, 2022.
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