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Nat Genet. 2005 Feb;37(2):161-5. Epub 2005 Jan 16.

Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.

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  • 1Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, Texas 75390-9046, USA.

Erratum in

  • Nat Genet. 2005 Mar;37(3):328.

Abstract

The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway, also cause hypercholesterolemia. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia 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.

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PMID:
15654334
[PubMed - indexed for MEDLINE]
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