Being Sensible About Cholesterol

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Science  11 Feb 2005:
Vol. 307, Issue 5711, pp. 819
DOI: 10.1126/science.307.5711.819b

As a recent advertising campaign reminds us, high cholesterol cannot be blamed solely on our unhealthy diets—the genes we inherit play a role as well. Analyzing a large multiethnic population in Texas, Cohen et al. found that individuals with exceptionally low levels of low-density lipoprotein cholesterol (LDL-C), or bad cholesterol, were far more likely than average to carry nonsense mutations in a gene called PCSK9; these mutations were found almost exclusively in African-Americans.

Missense mutations in PCSK9 had previously been identified as the cause of a rare inherited disorder characterized by extremely high cholesterol levels. The PCSK9 product is a serine protease (proprotein convertase subtilisin kexin 9), and an independent study of cultured human liver cells describes its role in cholesterol metabolism. By comparing the properties of cells overexpressing the wild type and a catalytically inactive form of the protease, Maxwell et al. conclude that PCSK9 accelerates the degradation of a protein that is a key determinant of plasma LDL-C levels, the LDL receptor. — PAK

Nature Genet. 37, 161 (2005); Proc. Natl. Acad. Sci. U.S.A. 102, 2069 (2005).

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