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Germline Mutations in CIDEB and Protection against Liver Disease

List of authors.
  • Niek Verweij, Ph.D.,
  • Mary E. Haas, Ph.D.,
  • Jonas B. Nielsen, M.D., Ph.D.,
  • Olukayode A. Sosina, Ph.D.,
  • Minhee Kim, Ph.D.,
  • Parsa Akbari, Ph.D.,
  • Tanima De, Ph.D.,
  • George Hindy, M.D., Ph.D.,
  • Jonas Bovijn, M.D., Ph.D.,
  • Trikaldarshi Persaud, B.S.,
  • Lawrence Miloscio, B.S.,
  • Mary Germino, Ph.D.,
  • Lampros Panagis, Ph.D.,
  • Kyoko Watanabe, Ph.D.,
  • Joelle Mbatchou, Ph.D.,
  • Marcus Jones, Ph.D.,
  • Michelle LeBlanc, Ph.D.,
  • Suganthi Balasubramanian, Ph.D.,
  • Craig Lammert, M.D.,
  • Sofia Enhörning, M.D., Ph.D.,
  • Olle Melander, M.D., Ph.D.,
  • David J. Carey, Ph.D.,
  • Christopher D. Still, M.D.,
  • Tooraj Mirshahi, Ph.D.,
  • Daniel J. Rader, M.D.,
  • Prodromos Parasoglou, Ph.D.,
  • Johnathon R. Walls, Ph.D.,
  • John D. Overton, Ph.D.,
  • Jeffrey G. Reid, Ph.D.,
  • Aris Economides, Ph.D.,
  • Michael N. Cantor, M.D.,
  • Brian Zambrowicz, Ph.D.,
  • Andrew J. Murphy, Ph.D.,
  • Goncalo R. Abecasis, Ph.D.,
  • Manuel A.R. Ferreira, Ph.D.,
  • Eriks Smagris, Ph.D.,
  • Viktoria Gusarova, Ph.D.,
  • Mark Sleeman, Ph.D.,
  • George D. Yancopoulos, M.D., Ph.D.,
  • Jonathan Marchini, Ph.D.,
  • Hyun M. Kang, Ph.D.,
  • Katia Karalis, M.D., Ph.D.,
  • Alan R. Shuldiner, M.D.,
  • Giusy Della Gatta, Ph.D.,
  • Adam E. Locke, Ph.D.,
  • Aris Baras, M.D.,
  • and Luca A. Lotta, M.D., Ph.D.



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.


We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.


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. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We 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 U per liter; 95% confidence interval [CI], −1.66 to −0.83; P=4.8×10−9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10−7). 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 (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic 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 buildup of large lipid droplets.


Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.)

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Funding and Disclosures

Supported by Regeneron Pharmaceuticals. Dr. Melander’s work is supported by the European Research Council (ERC-AdG-2019-885003), and Dr. Lammert’s work is supported by a grant from the National Institutes of Health (NIDDK K23DK11456). The U.K. Biobank resource (application ID 26041) was used in this research.

Disclosure forms provided by the authors are available with the full text of this article at

Drs. Verweij, Haas, Nielsen, Sosina, and Kim and Drs. Della Gatta, Locke, Baras, and Lotta contributed equally to this article.

Author Affiliations

From the Regeneron Genetics Center (N.V., M.E.H., J.B.N., O.A.S., M.K., P.A., T.D., G.H., J.B., T.P., L.M., K.W., J. Mbatchou, M.J., M.L., S.B., J.D.O., J.G.R., A.E., M.N.C., G.R.A., M.A.R.F., J. Marchini, H.M.K., K.K., A.R.S., G.D.G., A.E.L., A.B., L.A.L.), Regeneron Pharmaceuticals (M.G., L.P., P.P., J.R.W., B.Z., A.J.M., E.S., V.G., M.S., G.D.Y.), Tarrytown, NY; Indiana University School of Medicine, Indianapolis (C.L.); the Department of Clinical Sciences Malmö, Lund University, and the Department of Emergency and Internal Medicine, Skåne University Hospital — both in Malmö, Sweden (S.E., O.M.); and the Department of Molecular and Functional Genomics, Geisinger Health System, Danville (D.J.C., C.D.S., T.M.), and the Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.) — both in Pennsylvania.

Dr. Lotta can be contacted at or at the Regeneron Genetics Center, Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd., Tarrytown, NY 10591. Dr. Baras can be contacted at .

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