title: Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.
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.
authors.affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, Texas 75390-9046, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cohen
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Kotowski
authors.forename: Randall
authors.initials: R
authors.lastname: Graham
authors.forename: Christine Kim
authors.initials: CK
authors.lastname: Garcia
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D018389:Codon, Nonsense; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*; D001741:Black or African American
chemical_list: D008078:Cholesterol, LDL; D018389:Codon, Nonsense; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases