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Germline Mutations ...
Germline Mutations in CIDEB and Protection against Liver Disease
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- Verweij, Niek (author)
- Regeneron Pharmaceuticals, Inc.
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- Haas, Mary E. (author)
- Regeneron Pharmaceuticals, Inc.
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- Nielsen, Jonas B. (author)
- Regeneron Pharmaceuticals, Inc.
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- Sosina, Olukayode A. (author)
- Regeneron Pharmaceuticals, Inc.
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- Kim, Minhee (author)
- Regeneron Pharmaceuticals, Inc.
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- Akbari, Parsa (author)
- Regeneron Pharmaceuticals, Inc.
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- De, Tanima (author)
- Regeneron Pharmaceuticals, Inc.
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- Hindy, George (author)
- Regeneron Pharmaceuticals, Inc.
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- Bovijn, Jonas (author)
- Regeneron Pharmaceuticals, Inc.
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- Persaud, Trikaldarshi (author)
- Regeneron Pharmaceuticals, Inc.
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- Miloscio, Lawrence (author)
- Regeneron Pharmaceuticals, Inc.
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- Germino, Mary (author)
- Regeneron Pharmaceuticals, Inc.
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- Panagis, Lampros (author)
- Regeneron Pharmaceuticals, Inc.
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- Watanabe, Kyoko (author)
- Regeneron Pharmaceuticals, Inc.
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- Mbatchou, Joelle (author)
- Regeneron Pharmaceuticals, Inc.
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- Jones, Marcus (author)
- Regeneron Pharmaceuticals, Inc.
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- LeBlanc, Michelle (author)
- Regeneron Pharmaceuticals, Inc.
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- Balasubramanian, Suganthi (author)
- Regeneron Pharmaceuticals, Inc.
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- Lammert, Craig (author)
- Indiana University
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- Enhörning, Sofia (author)
- Lund University,Lunds universitet,Perinatal och kardiovaskulär epidemiologi,Forskargrupper vid Lunds universitet,Perinatal and cardiovascular epidemiology,Lund University Research Groups,Skåne University Hospital
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- Melander, Olle (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups,Skåne University Hospital
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- Carey, David J. (author)
- Geisinger Health System
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- Still, Christopher D. (author)
- Geisinger Health System
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- Mirshahi, Tooraj (author)
- Geisinger Health System
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- Rader, Daniel J. (author)
- University of Pennsylvania
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- Parasoglou, Prodromos (author)
- Regeneron Pharmaceuticals, Inc.
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- Walls, Johnathon R. (author)
- Regeneron Pharmaceuticals, Inc.
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- Overton, John D. (author)
- Regeneron Pharmaceuticals, Inc.
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- Reid, Jeffrey G. (author)
- Regeneron Pharmaceuticals, Inc.
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- Economides, Aris (author)
- Regeneron Pharmaceuticals, Inc.
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- Cantor, Michael N. (author)
- Regeneron Pharmaceuticals, Inc.
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- Zambrowicz, Brian (author)
- Regeneron Pharmaceuticals, Inc.
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- Murphy, Andrew J. (author)
- Regeneron Pharmaceuticals, Inc.
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- Abecasis, Goncalo R. (author)
- Regeneron Pharmaceuticals, Inc.
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- Ferreira, Manuel A.R. (author)
- Regeneron Pharmaceuticals, Inc.
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- Smagris, Eriks (author)
- Regeneron Pharmaceuticals, Inc.
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- Gusarova, Viktoria (author)
- Regeneron Pharmaceuticals, Inc.
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- Sleeman, Mark (author)
- Regeneron Pharmaceuticals, Inc.
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- Yancopoulos, George D. (author)
- Regeneron Pharmaceuticals, Inc.
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- Marchini, Jonathan (author)
- Regeneron Pharmaceuticals, Inc.
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- Kang, Hyun M. (author)
- Regeneron Pharmaceuticals, Inc.
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- Karalis, Katia (author)
- Regeneron Pharmaceuticals, Inc.
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- Shuldiner, Alan R. (author)
- Regeneron Pharmaceuticals, Inc.
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- Della Gatta, Giusy (author)
- Regeneron Pharmaceuticals, Inc.
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- Locke, Adam E. (author)
- Regeneron Pharmaceuticals, Inc.
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- Baras, Aris (author)
- Regeneron Pharmaceuticals, Inc.
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- Lotta, Luca A. (author)
- Regeneron Pharmaceuticals, Inc.
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Regeneron Pharmaceuticals, Inc Indiana University (creator_code:org_t)
- 2022
- 2022
- English 13 s.
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In: New England Journal of Medicine. - 0028-4793. ; 387:4, s. 332-344
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Verweij, Niek
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Haas, Mary E.
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Nielsen, Jonas B ...
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Sosina, Olukayod ...
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Kim, Minhee
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Akbari, Parsa
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show more...
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De, Tanima
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Hindy, George
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Bovijn, Jonas
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Persaud, Trikald ...
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Miloscio, Lawren ...
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Germino, Mary
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Panagis, Lampros
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Watanabe, Kyoko
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Mbatchou, Joelle
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Jones, Marcus
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LeBlanc, Michell ...
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Balasubramanian, ...
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Lammert, Craig
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Enhörning, Sofia
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Melander, Olle
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Carey, David J.
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Still, Christoph ...
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Mirshahi, Tooraj
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Rader, Daniel J.
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Parasoglou, Prod ...
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Walls, Johnathon ...
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Overton, John D.
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Reid, Jeffrey G.
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Economides, Aris
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Cantor, Michael ...
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Zambrowicz, Bria ...
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Murphy, Andrew J ...
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Abecasis, Goncal ...
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Ferreira, Manuel ...
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Smagris, Eriks
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Gusarova, Viktor ...
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Sleeman, Mark
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Yancopoulos, Geo ...
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Marchini, Jonath ...
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Kang, Hyun M.
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Karalis, Katia
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Shuldiner, Alan ...
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Della Gatta, Giu ...
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Locke, Adam E.
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Baras, Aris
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Lotta, Luca A.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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New England Jour ...
- By the university
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Lund University