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A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Emdin, Connor A ; Haas, Mary E ; Khera, Amit V ; Aragam, Krishna ; Chaffin, Mark ; Klarin, Derek ; Hindy, George ; Jiang, Lan ; Wei, Wei-Qi ; Feng, Qiping ; Karjalainen, Juha ; Havulinna, Aki ; Kiiskinen, Tuomo ; Bick, Alexander ; Ardissino, Diego ; Wilson, James G ; Schunkert, Heribert ; McPherson, Ruth ; Watkins, Hugh ; Elosua, Roberto ; Bown, Matthew J ; Samani, Nilesh J ; Baber, Usman ; Erdmann, Jeanette ; Gupta, Namrata ; Danesh, John ; Saleheen, Danish ; Chang, Kyong-Mi ; Vujkovic, Marijana ; Voight, Ben ; Damrauer, Scott ; Lynch, Julie ; Kaplan, David ; Serper, Marina ; Tsao, Philip ; Mercader, Josep ; Hanis, Craig ; Daly, Mark ; Denny, Joshua ; Gabriel, Stacey ; Kathiresan, Sekar Murdock, Deborah G.

PLoS genetics, 2020-04, Vol.16 (4), p.e1008629 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease
Autor: Emdin, Connor A ; Haas, Mary E ; Khera, Amit V ; Aragam, Krishna ; Chaffin, Mark ; Klarin, Derek ; Hindy, George ; Jiang, Lan ; Wei, Wei-Qi ; Feng, Qiping ; Karjalainen, Juha ; Havulinna, Aki ; Kiiskinen, Tuomo ; Bick, Alexander ; Ardissino, Diego ; Wilson, James G ; Schunkert, Heribert ; McPherson, Ruth ; Watkins, Hugh ; Elosua, Roberto ; Bown, Matthew J ; Samani, Nilesh J ; Baber, Usman ; Erdmann, Jeanette ; Gupta, Namrata ; Danesh, John ; Saleheen, Danish ; Chang, Kyong-Mi ; Vujkovic, Marijana ; Voight, Ben ; Damrauer, Scott ; Lynch, Julie ; Kaplan, David ; Serper, Marina ; Tsao, Philip ; Mercader, Josep ; Hanis, Craig ; Daly, Mark ; Denny, Joshua ; Gabriel, Stacey ; Kathiresan, Sekar
Murdock, Deborah G.
Assuntos: Alanine ; Alanine transaminase ; Alkaline phosphatase ; Alleles ; Biology and Life Sciences ; Biomedical research ; Blood levels ; Cardiology ; Cholesterol ; Cholesterol, LDL - blood ; Cirrhosis ; Computed tomography ; Coronary Artery Disease - genetics ; Datasets as Topic ; Departments ; Epidemiology ; Fatty liver ; Fatty Liver - blood ; Fatty Liver - enzymology ; Fatty Liver - genetics ; Fatty Liver - prevention & control ; Female ; Funding ; Gene frequency ; Genetic Predisposition to Disease ; Homozygote ; Hospitals ; Humans ; Informatics ; Liver - enzymology ; Liver Cirrhosis - blood ; Liver Cirrhosis - enzymology ; Liver Cirrhosis - genetics ; Liver Cirrhosis - prevention & control ; Liver Cirrhosis, Alcoholic - blood ; Liver Cirrhosis, Alcoholic - enzymology ; Liver Cirrhosis, Alcoholic - genetics ; Liver Cirrhosis, Alcoholic - prevention & control ; Liver diseases ; Loss of Function Mutation - genetics ; Low density lipoprotein ; Male ; Medical schools ; Medicine ; Medicine and Health Sciences ; Middle Aged ; Mitochondria ; Mitochondrial Proteins - genetics ; Mutation, Missense - genetics ; Oxidoreductases - genetics ; Population genetics ; Public health ; Social Sciences ; Transaminase
É parte de: PLoS genetics, 2020-04, Vol.16 (4), p.e1008629
Notas: new_version
CAE reports consulting fees from Navitor Pharma, Novartis and Deerfield Management. AVK has received research grants from IBM Research and the Novartis Institute for Biomedical Research and has served as a consultant to or received honoraria from Color Genomics, Illumina, Novartis, Maze Therapeutics, and Navitor Pharmaceuticals; and has a patent related to a genetic risk predictor (20190017119). SK is an employee of Verve Therapeutics and has received a research grant from Bayer Healthcare; and consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, MedGenome, Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, Quest Diagnostics, Color Genomics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics, Catabasis Pharmaceuticals, Verve Therapeutics and Maze Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Descrição: Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
Editor: United States: Public Library of Science
Idioma: Inglês

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A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

United States: Public Library of Science

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