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

• Published in: Nature genetics Vol. 37; no. 2; pp. 161 - 165
• Main Authors: Cohen, Jonathan, Pertsemlidis, Alexander, Kotowski, Ingrid K, Graham, Randall, Garcia, Christine Kim, Hobbs, Helen H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2005; Nature Publishing Group
• Subjects: Adult; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Black or African American; Black People - genetics; Cancer Research; Care and treatment; Cholesterol; Cholesterol, LDL - blood; Codon, Nonsense; Control; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Human Genetics; Humans; Hypercholesterolemia; Identification and classification; letter; Low density lipoprotein receptors; Low density lipoproteins; Male; Middle Aged; Minority & ethnic groups; Mutation; Pedigree; Physiological aspects; Proprotein Convertase 9; Proprotein Convertases; Risk factors; Serine Endopeptidases - genetics; United States; Nonsense mutation; Cholesterol LDL; African
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1509

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 1 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 , 6 , 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.