1. Rare mutations in CIDEB are associated with a decreased risk of developing liver cirrhosis.

2. Further, rare mutations in CIDEB are associated with a decreased risk of nonalcoholic fatty liver disease.

Evidence Rating Level: 1 (Excellent)

Study Rundown: For patients with obesity and nonalcoholic fatty liver disease, the risk of progression to steatohepatitis and cirrhosis can vary significantly. Emerging literature suggests that genetic factors may play a key role in these differences. For example, a recent analysis demonstrated that a loss-of-function variant in HSD17B13 conferred protection from liver disease, though there is a gap in knowledge as to understanding the contribution of rare coding variants to liver phenotypes. The present study evaluated the impact of germline mutations in CIDEB on the risk of developing liver disease. Overall, the study found that persons with rare germline mutations in CIDEB had substantial protection from both liver damage and liver disease during the study period. This study was limited by underrepresenting persons of non-European ancestry in their study cohort and limited precision in estimates for binary liver outcomes. Nevertheless, the study’s findings are significant, as they demonstrate that rare germline mutations in CIDEB can confer significant protection from liver damage and subsequent liver disease.

Click to read the study in NEJM

Relevant Reading: Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency

In-Depth [genetic association analysis]: This multistage exome sequencing and genetic association analysis sequenced more than 500,000 people to identify genes for which the burden of rare coding alleles was associated with liver phenotypes. Particularly, liver disease and damage were evaluated. Patients included were from cohort studies in the UK Biobank, the Geisinger Health System, the Penn Medicine BioBank, and the Mount Sinai BioBank. The primary outcome measured was the classification of genotypes, with clinical phenotypes defined from clinical biochemical measurements of aminotransferases and liver-fat percentages derived from MRI. Outcomes in the primary analysis were assessed via fitting linear regression models for quantitative traits or Firth bias-corrected logistic regression models for binary traits. The primary analysis found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and increased risk of liver disease. They also found that variants in CIDEB had a protective effect. Loss-of-function variants plus missense variants in CIDEB were associated with a decreased alanine aminotransferase level (beta per allele, -1.24 U per liter; 95% Confidence Interval [CI], -1.66 to -0.83), and with 33% lower odds of liver disease of any cause (odds ratio, 0.67; 95% CI 0.57 to 0.79). These rare coding variants in CIDEB were also associated with a decreased risk of liver disease over different underlying causes, including cirrhosis (OR 0.5, 95% CI, 0.36 to 0.70). Overall, this study demonstrates that rare germline mutations in CIDEB can confer substantial protection from liver damage and liver disease.

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