Journal
NATURE GENETICS
Volume 37, Issue 2, Pages 161-165Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng1509
Keywords
-
Categories
Ask authors/readers for more resources
The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR1 or its ligand (APOB)(2) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway(3), also cause hypercholesterolemia(4). These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia(5-7) by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (<0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol. These data indicate that common sequence variations have large effects on plasma cholesterol levels in selected populations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available