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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

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 hypercholesterolemia5,6,7 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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References

  1. Goldstein, J., Hobbs, H. & Brown, M. Familial hypercholesterolemia. in The Metabolic and Molecular Bases of Inherited Disease, vol. II (eds. Scriver, C., Beaudet, A., Sly, W. & Valle, D.) 2863–2913 (McGraw Hill, New York, 2001).

    Google Scholar 

  2. Innerarity, T.L. et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J. Lipid Res. 31, 1337–1349 (1990).

    CAS  PubMed  Google Scholar 

  3. Seidah, N.G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA 100, 928–933 (2003).

    Article  CAS  Google Scholar 

  4. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    Article  CAS  Google Scholar 

  5. Maxwell, K.N. & Breslow, J.L. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl. Acad. Sci. USA 101, 7100–7105 (2004).

    Article  CAS  Google Scholar 

  6. Park, S.W., Moon, Y.A. & Horton, J.D. Post-transcriptional regulation of LDL receptor protein by proprotein convertase subtilisin/kexin type 9a (PCSK9) in mouse liver. J. Biol. Chem. 279, 50630–50638 (2004).

    Article  CAS  Google Scholar 

  7. Benjannet, S. et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the LDLR and LDL-cholesterol. J. Biol. Chem. 279, 48865–48875 (2004).

    Article  CAS  Google Scholar 

  8. Timms, K.M. et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum. Genet. 114, 349–353 (2004).

    Article  CAS  Google Scholar 

  9. Leren, T.P. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin. Genet. 65, 419–422 (2004).

    Article  CAS  Google Scholar 

  10. Victor, R.G. et al. A population-based probability sample for the multidisciplinary study of ethnic disparities in cardiovascular disease: recruitment and validation in the Dallas Heart Study. Am. J. Cardiol. 93, 1473–1480 (2004).

    Article  Google Scholar 

  11. Miettinen, T.A., Tilvis, R.S. & Kesaniemi, Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am. J. Epidemiol. 131, 20–31 (1990).

    Article  CAS  Google Scholar 

  12. Otvos, J.D. Measurement of lipoprotein subclass profiles by nuclear magnetic resonance spectroscopy. in Handbook of Lipoprotein Testing, Ch. 28 (eds. Rifai, N., Warnick, G.R. and Dominiczack, M.H.) 497–508 (AACC Press, Washington, DC, 1997).

    Google Scholar 

  13. Horton, J.D. et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA 95, 5987–5992 (1998).

    Article  CAS  Google Scholar 

  14. Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    Article  CAS  Google Scholar 

  15. Shioji, K. et al. Genetic variants in PCSK9 affect the cholesterol level in Japanese. J. Hum. Genet. 49, 109–114 (2004).

    Article  CAS  Google Scholar 

  16. Hofer, F. et al. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc. Natl. Acad. Sci. USA 91, 1839–1842 (1994).

    Article  CAS  Google Scholar 

  17. Agnello, V., Abel, G., Elfahal, M., Knight, G.B. & Zhang, Q.X. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc. Natl. Acad. Sci. USA 96, 12766–12771 (1999).

    Article  CAS  Google Scholar 

  18. Mostaza, J.M., Schulz, I., Vega, G.L. & Grundy, S.M. Comparison of pravastatin with crystalline nicotinic acid monotherapy in treatment of combined hyperlipidemia. Am. J. Cardiol. 79, 1298–1301 (1997).

    Article  CAS  Google Scholar 

  19. Wilund, K.R. et al. Plant sterol levels are not associated with atherosclerosis in mice and men. Arterioscler. Thromb. Vasc. Biol. 24, 2326–2332 (2004).

    Article  CAS  Google Scholar 

  20. Marcovina, S.M., Albers, J.J., Gabel, B., Koschinsky, M.L. & Gaur, V.P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin. Chem. 41, 246–255 (1995).

    CAS  PubMed  Google Scholar 

  21. Qin, Z.S., Niu, T. & Liu, J.S. Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am. J. Hum. Genet. 71, 1242–1247 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/ng1509

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