CIDEB – Cirrhosis of Liver

This summary evaluates the association between rare germline variants in CIDEB and a reduced risk of cirrhosis of liver. A large-scale exome sequencing study involving over 542,000 individuals identified that carriers of rare predicted loss‑of‑function and missense variants in CIDEB show a 33% reduction in the odds of liver disease (PMID:35939579). These findings provide strong clinical validity to the protective role of CIDEB in liver disease.

Genetic evidence points to an autosomal dominant effect, as each allele carrying a rare variant appears to contribute to the protective phenotype. In the NEJM study, this association was observed in 24,944 patients with liver disease and 490,636 controls, supporting a robust statistical correlation between CIDEB variants and lower alanine aminotransferase levels (PMID:35939579). Although extended familial segregation data were not provided, the large cohort size compensates with statistical power.

While the burden of rare variants in CIDEB has been highlighted, no specific HGVS‐formatted variant string meeting the criteria (i.e. a complete coding change starting with “c.” and containing a “(p…)” description with three‑letter amino acid codes) was delineated in these studies. Therefore, the variant spectrum for CIDEB remains described qualitatively as comprising predicted loss‑of‑function and missense changes.

Complementary functional evidence further supports the gene–disease association. In vitro experiments, including siRNA knockdown in human hepatoma cell lines, demonstrated that reduced CIDEB expression prevented the accumulation of large lipid droplets. Additionally, a study in a porcine model identified a novel splicing variant that, along with tissue expression analyses, provided insights into CIDEB’s role in lipid metabolism (PMID:27207838).

It is notable that conflicting evidence exists. A separate study investigating germline variation in several genes, including CIDEB, did not find associations with markers of liver disease in the context of fatty liver disease phenotypes (PMID:35474605). These differences may reflect variations in study design, patient cohorts, or phenotypic definitions; however, the protective association with cirrhosis remains compelling in the larger exome sequencing analysis.

In summary, integration of massive genetic data with supportive functional studies presents a coherent narrative for the protective effect of rare CIDEB variants against cirrhosis of liver. The strength of the evidence supports its utility in diagnostic decision‑making, commercial application, and further research into therapeutic targets.

Key Take‑Home: Rare CIDEB variants offer a promising avenue as protective modifiers in cirrhosis, underscoring the gene’s clinical relevance and translational potential.

References

• The New England journal of medicine • 2022 • Germline Mutations in CIDEB and Protection against Liver Disease PMID:35939579
• Biochemical and biophysical research communications • 2016 • Molecular cloning, genomic organization, chromosome mapping, tissues expression pattern and identification of a novel splicing variant of porcine CIDEb gene PMID:27207838
• Liver international : official journal of the International Association for the Study of the Liver • 2022 • A minority of somatically mutated genes in pre‑existing fatty liver disease have prognostic importance in the development of NAFLD PMID:35474605

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