Liver and Bile

N Engl J Med. 2022;387(4):332–44

Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P, De T, Hindy G, Bovijn J, Persaud T, Miloscio L, Germino M, Panagis L, Watanabe K, Mbatchou J, Jones M, LeBlanc M, Balasubramanian S, Lammert C, Enhörning S, Melander O, Carey DJ, Still CD, Mirshahi T, Rader DJ, Parasoglou P, Walls JR, Overton JD, Reid JG, Economides A, Cantor MN, Zambrowicz B, Murphy AJ, Abecasis GR, Ferreira MAR, Smagris E, Gusarova V, Sleeman M, Yancopoulos GD, Marchini J, Kang HM, Karalis K, Shuldiner AR, Della Gatta G, Locke AE, Baras A, Lotta LA

Germline mutations in CIDEB and protection against liver disease

Background: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.
Methods: The authors performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. They conducted in vitro experiments to further characterize associations.
Results: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. It was found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. It was also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 IU/l, 95% confidence interval [CI]: -1.66 to -0.83; p = 4.8 x 10-9) and with 33% lower odds of liver disease of any cause (odds ratio [OR] per allele = 0.67, 95% CI: 0.57–0.79; p = 9.9 x 10-7). Rare coding variants in CIDEB were associated with a 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). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased non-alcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI: -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the build-up of large lipid droplets.

Conclusions: Rare germline mutations in CIDEB conferred substantial protection from liver disease.

DOI: 10.1056/nejmoa2117872