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.
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Our findings are in line with data from PCSK9 inhibitor clinical trials and from observations that people carrying loss-of-function mutations of PCSK9 gene have no signs of neurological defects.
“Our findings are in line with data from PCSK9 inhibitor clinical trials (Giugliano et al., 2017; Mannarino et al., 2018; Gencer et al., 2020; Ray et al., 2020) and from observations that people carrying loss-of-function mutations of the PCSK9 gene have no signs of neurological defects (Cohen et al., 2005, 2006; Zhao et al., 2006; Hooper et al., 2007; Mefford et al., 2018).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Cohen et al., 2005
PCSK9 loss-of-function mutations are associated with a marked increase of hepatic LDLR levels and a significant decrease of plasma LDL cholesterol levels.
“loss-of-function (LOF) mutations of PCSK9 are associated with a marked increase of hepatic LDLR levels and a significant decrease of plasma LDL cholesterol levels”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Cohen et al 2005
Hobbs and Cohen identified low-frequency common variants in PCSK9 at 0.5 to 1%, which allowed epidemiological research documenting a protective effect on myocardial infarction.
“Hobbs and Cohen sequenced the gene (126, 127) and identified low-frequency common variants (0.5 to 1%), which allowed epidemiological research documenting a protective effect on myocardial infarction (128).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [127]
The gene encoding PCSK9 contains very rare mutations causing autosomal dominant hypercholesterolemia and high-frequency common variants with modest effects.
“The gene encoding PCSK9 contains very rare mutations causing autosomal dominant hypercholesterolemia (discovered by linkage analysis), as well as high-frequency common variants with modest effects.”
From Genetic Mapping in Human Disease (2008) · cites this paper as [127]
Profiling plasma lipids in large populations has uncovered sequence variations that substantially impact lipid phenotypes.
“Profiling plasma lipids in large populations has uncovered sequence variations that substantially impact lipid phenotypes (Cohen et al., 2005; Teslovich et al., 2010).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Cohen et al., 2005
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- Authors
- Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hobbs, Helen H
- Venue
- Nature Genetics
- Published
- 2005-01-16
- Volume
- 37
- Issue
- 2
- Pages
- 161-165
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2064994526
- Cited by
- 1,381
- References
- 25
- Citations by year
- 2026: 44 · 2025: 51 · 2024: 45 · 2023: 68 · 2022: 80 · 2021: 94 · 2020: 74 · 2019: 79 · 2018: 89 · 2017: 96 · 2016: 79 · 2015: 94 · 2014: 75 · 2013: 82 · 2012: 58
- FWCI
- 47.87
- Type
- journal article
- Language
- en
- Update notices
- erratum (2005-03-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- PCSK9, nonsense mutation, LDL cholesterol, African Americans, hypercholesterolemia, LDL receptor, loss-of-function mutations, plasma cholesterol levels, genetic variants
- MeSH terms
- Proprotein Convertase 9, Adult, Black or African American, Female, Haplotypes, Humans, Cholesterol, LDL, Male, Middle Aged, Pedigree, Serine Endopeptidases, Codon, Nonsense, Proprotein Convertases, Black People
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