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

A Corrigendum to this article was published on 01 March 2005


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 hypercholesterolemia5,6,7 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.

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Figure 1: Functional domains and haplotypes of PCSK9.
Figure 2: Distribution of plasma LDL-C levels in African American subjects in the Dallas Heart Study without (top) and with (bottom) a nonsense mutation in PCSK9.
Figure 3: Families of probands with nonsense mutations in PCSK9.

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We thank the Dallas Heart Study Investigators10, especially R. Victor for spearheading the study, D. Willett for designing and managing the database and S. Grundy and G. Vega for measuring plasma lipoprotein levels; B. Gilbert, H. Brookman and T. Eversole for collecting blood from families and processing the samples; T. Hyatt, S. Niu and C.J. Horton for technical assistance; R. Cooper for providing genomic DNA samples from Chicago and Nigeria; and M.S. Brown, J.L. Goldstein, J. Horton, A. Sparks and D. Cox for discussions. This work was supported by grants from the Donald W. Reynolds Foundation, The Perot Family Fund, the LeDucq Foundation and the National Institutes of Health. C.K.G. is supported by the Parker B. Francis Family Foundation.

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Correspondence to Helen H Hobbs.

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Cohen, J., Pertsemlidis, A., Kotowski, I. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37, 161–165 (2005).

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