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

Nat Genet. 2005 Feb;37(2):161-5. doi: 10.1038/ng1509. Epub 2005 Jan 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • African Continental Ancestry Group / genetics*
  • Cholesterol, LDL / blood*
  • Codon, Nonsense*
  • Female
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases / genetics*

Substances

  • Cholesterol, LDL
  • Codon, Nonsense
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases