Gene Variants Found to Protect Against Liver Disease

Laird Harrison

August 09, 2022

Rare gene variants are associated with a reduced risk for multiple types of liver disease, including cirrhosis, researchers say.

People with certain variants in the gene CIDEB are one-third less likely to develop any sort of liver disease, according to Aris Baras, MD, a senior vice president at Regeneron, and colleagues.

"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 Baras in a press release.

Baras and colleagues published the finding in The New England Journal of Medicine .

The finding follows on a similar discovery about a common variant in the gene HSD17B13. Treatments targeting this gene are being tested in clinical trials.

To search for more such genes, the researchers analyzed human exomes — the part of the genome that codes for proteins — to look for associations between gene variants and liver function.

The researchers used exome sequencing on 542,904 people from the UK Biobank, the Geisinger Health System MyCode cohort, and other datasets.

They found that coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk for liver disease.

But variants in CIDEB were associated with decreased levels of alanine aminotransferase, a biomarker of hepatocellular injury. And they were associated with a decreased risk for liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57-0.79).

The CIDEB variants were present in only 0.7% of the persons in the study.

Zeroing in on various kinds of liver disease, the researchers found that the CIDEB variants were associated with a reduced risk for alcoholic liver disease, nonalcoholic liver disease, any liver cirrhosis, alcoholic liver cirrhosis, nonalcoholic liver cirrhosis, and viral hepatitis.

In 3599 patients who had undergone bariatric surgery, variants in CIDEB were associated with a reduced nonalcoholic fatty liver disease activity score of -0.98 beta per allele in score units, where scores range from 0-8, with a higher score indicating more severe disease.

In patients for whom MRI data were available, those with rare coding variants in CIDEB had lower proportions of liver fat. However, percentage of liver fat did not fully explain the reduced risk for liver disease.

Pursuing another line of investigation, the researchers found that they could prevent the buildup of large lipid droplets in oleic acid-treated human hepatoma cell lines by silencing the CIDEB gene using small interfering RNA.

The association was particularly strong among people with higher body mass indices and type 2 diabetes.

The associations with the rare protective CIDEB variants were consistent across ancestries, but people of non-European ancestry, who might be disproportionately affected by liver disease, were underrepresented in the database, the researchers note.

The study was supported by Regeneron Pharmaceuticals, which also employed several of the researchers.

N Engl J Med. Published online July 28, 2022. Abstract

Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH

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