Rare Mutations Linked to Protection Against Liver DiseaseJuly 28, 2022
Rare germline mutations in the CIDEB gene appeared to protect against liver disease, according to a large human genetics study.
In a multi-stage analysis using exome sequencing in over half a million participants, rare predicted loss-of-function CIDEB variants and missense variants were linked to lower alanine aminotransferase (ALT) levels (beta per allele -1.24 U per liter, 95% CI -1.66 to -0.83) and lower odds of liver disease of any cause (OR per allele 0.67, 95% CI 0.57-0.79) compared with non-carriers, reported Luca Lotta, MD, PhD, of Regeneron Pharmaceuticals in Tarrytown, New York, and colleagues.
Furthermore, rare coding variants in CIDEB were tied to decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (OR per allele 0.50, 95% CI 0.36-0.70), the authors wrote in the New England Journal of Medicine.
“CIDEB is a critical player for liver disease in humans and blocking it may help prevent or treat liver disease,” Lotta told MedPage Today. “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.”
Among a subgroup of 3,599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were tied to a decreased nonalcoholic fatty liver disease (NAFLD) activity score (beta per allele in score units -0.98, 95% CI -1.54 to -0.41), the authors said.
On the other hand, Lotta and team pointed out that rare coding variants in ABCB4, APOB, SLC30A10, and TM6SF2 — known to be related to NAFLD — were all associated with higher levels of aminotransferases and a higher risk of developing liver disease.
“In patients with obesity and nonalcoholic fatty liver disease, the risk of progression to steatohepatitis and cirrhosis has a high degree of interindividual variability in which genetic factors play a key role,” they noted.
The authors also found that among human hepatoma cell lines challenged with oleate, silencing CIDEB with small interfering RNA prevented the buildup of large lipid droplets by reducing their size.
For this study, Lotta and colleagues included 542,904 participants with data on liver aminotransferase levels from the U.K. Biobank and the Geisinger Health System MyCode cohorts. Of these patients, 24,944 had liver disease and 490,636 did not. Most participants had European ancestry.
In their multi-stage approach, the researchers first estimated associations between the burden of rare coding alleles and ALT levels for each gene, then corroborated those associations using aspartate aminotransferase levels, and estimated the associations with liver disease in the third stage, which also included participants from the Malmö Diet and Cancer Study, the University of Pennsylvania Penn Medicine BioBank, and the Mount Sinai BioMe BioBank.
Even though associations with CIDEB variants were consistent across ancestries, Lotta and team acknowledged that participants of non-European ancestry, who may be disproportionately affected by liver disease, were relatively underrepresented in their analysis.
Furthermore, “[a]lthough our analysis suggests that lifelong exposure to heterozygous loss of function in CIDEB is associated with halving of the risk of cirrhosis, it is not known whether shorter-term and near-complete pharmacologic inhibition of CIDEB will yield clinically meaningful effects on the risk of liver disease or its progression,” the group noted.
This study was supported by Regeneron Pharmaceuticals.
Lotta reported relationships with Regeneron. Lotta and co-authors also reported sharing a pending patent for the treatment of liver disease with CIDEB inhibitors and another pending patent for the treatment of liver disease with GPAM inhibitors.
Co-authors reported relationships with Regeneron, the European Research Council, Broad Institute of MIT, Harvard, NIH Clinical Center, Alnylam Pharmaceuticals, Verve, Pfizer, Novartis, VascularStrategies, Staten Biotechnology, and the National Institutes of Health.