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

Jonathan Cohen, Alexander Pertsemlidis, Ingrid K. Kotowski, Randall Graham, Christine Kim Garcia, Helen H. Hobbs

Research output: Contribution to journalArticle

870 Scopus citations

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 LDLR1 or its ligand (APOB)2 cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway3, also cause hypercholesterolemia4. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia5-7 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.

Original languageEnglish (US)
Pages (from-to)161-165
Number of pages5
JournalNature genetics
Volume37
Issue number2
DOIs
StatePublished - Feb 1 2005

ASJC Scopus subject areas

  • Genetics

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