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Germline Mutations in CIDEB and Protection against Liver Disease

Verweij, Niek ; Haas, Mary E. ; Nielsen, Jonas B. ; Sosina, Olukayode A. ; Kim, Minhee ; Akbari, Parsa ; De, Tanima ; Hindy, George ; Bovijn, Jonas and Persaud, Trikaldarshi , et al. (2022) In New England Journal of Medicine 387(4). p.332-344
Abstract

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 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. 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. We found that... (More)

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

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type
Contribution to journal
publication status
published
subject
in
New England Journal of Medicine
volume
387
issue
4
pages
13 pages
publisher
Massachusetts Medical Society
external identifiers
  • pmid:35939579
  • scopus:85135417712
ISSN
0028-4793
DOI
10.1056/NEJMoa2117872
language
English
LU publication?
yes
id
8c769186-5085-4c35-bff2-aefeb5eda60a
date added to LUP
2022-10-20 15:18:36
date last changed
2024-04-18 15:04:07
@article{8c769186-5085-4c35-bff2-aefeb5eda60a,
  abstract     = {{<p>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 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. 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. 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<sup>-9</sup>) 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<sup>-7</sup>). 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. CONCLUSIONS Rare germline mutations in CIDEB conferred substantial protection from liver disease.</p>}},
  author       = {{Verweij, Niek and Haas, Mary E. and Nielsen, Jonas B. and Sosina, Olukayode A. and Kim, Minhee and Akbari, Parsa and De, Tanima and Hindy, George and Bovijn, Jonas and Persaud, Trikaldarshi and Miloscio, Lawrence and Germino, Mary and Panagis, Lampros and Watanabe, Kyoko and Mbatchou, Joelle and Jones, Marcus and LeBlanc, Michelle and Balasubramanian, Suganthi and Lammert, Craig and Enhörning, Sofia and Melander, Olle and Carey, David J. and Still, Christopher D. and Mirshahi, Tooraj and Rader, Daniel J. and Parasoglou, Prodromos and Walls, Johnathon R. and Overton, John D. and Reid, Jeffrey G. and Economides, Aris and Cantor, Michael N. and Zambrowicz, Brian and Murphy, Andrew J. and Abecasis, Goncalo R. and Ferreira, Manuel A.R. and Smagris, Eriks and Gusarova, Viktoria and Sleeman, Mark and Yancopoulos, George D. and Marchini, Jonathan and Kang, Hyun M. and Karalis, Katia and Shuldiner, Alan R. and Della Gatta, Giusy and Locke, Adam E. and Baras, Aris and Lotta, Luca A.}},
  issn         = {{0028-4793}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{4}},
  pages        = {{332--344}},
  publisher    = {{Massachusetts Medical Society}},
  series       = {{New England Journal of Medicine}},
  title        = {{Germline Mutations in CIDEB and Protection against Liver Disease}},
  url          = {{http://dx.doi.org/10.1056/NEJMoa2117872}},
  doi          = {{10.1056/NEJMoa2117872}},
  volume       = {{387}},
  year         = {{2022}},
}