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

Emdin, C. A.; Haas, M.; Khera, A. V.; Aragam, K.; Chaffin, M.; Jiang, L.; Wei, W.-Q.; Feng, Q.; Karjalainen, J.; Havulinna, A.; Kiiskinen, T.; Bick, A.; Ardissino, D.; Wilson, J. G.; Schunkert, H.; McPherson, R.; Watkins, H.; Elosua, R.; Bown, M. J.; Samani, N. J.; Baber, U.; Erdmann, J.; Gupta, N.; Danesh, J.; Saleheen, D.; Daly, M.; Denny, J.; Gabriel, S.; Kathiresan, S.

doi:10.1101/594523

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bioRxiv · 10.1101/594523

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

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Abstract

Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10-8). 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 (-0.012 SD, 1.4*10-8), alkaline phosphatase (-0.019 SD, 6.6*10-9), total cholesterol (-0.037 SD, p=1*10-18) and LDL cholesterol (-0.035 SD, p=7.3*10-16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

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Emdin, C. A., Haas, M., Khera, A. V., Aragam, K., Chaffin, M., Jiang, L., Wei, W.-Q., Feng, Q., Karjalainen, J., Havulinna, A., Kiiskinen, T., Bick, A., Ardissino, D., Wilson, J. G., Schunkert, H., McPherson, R., Watkins, H., Elosua, R., Bown, M. J., Samani, N. J., Baber, U., Erdmann, J., Gupta, N., Danesh, J., Saleheen, D., Daly, M., Denny, J., Gabriel, S., Kathiresan, S.. 2019-03-31. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. https://doi.org/10.1101/594523

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