Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy
Abstract
Objective— The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene encodes a proprotein convertase that causes degradation of cell surface low-density lipoprotein receptors (LDLRs). Mutations in the PCSK9 gene that disrupt the normal function of PCSK9 could therefore result in increased number of LDLRs and hypocholesterolemia. Also, the cholesterol-lowering effect of statins could be increased in subjects carrying mutations in the PCSK9 gene. Methods and Results— We have screened 38 unrelated hypocholesterolemic subjects as well as 25 unrelated familial hypercholesterolemia (FH) heterozygotes who responded particularly well to statin therapy for mutations in the 12 exons of the PCSK9 gene by DNA sequencing. Six of the 38 (15.8%) hypocholesterolemic subjects were heterozygous for 1 of the 3 mutations R46L, G106R, or R237W in the PCSK9 gene. In the group of 25 FH heterozygotes who responded particularly well to statin therapy, 3 (8.8%) were heterozygous for mutations R46L or N157K in the PCSK9 gene. None of 441 hypercholesterolemic subjects without mutations in the LDLR gene or in the apolipoprotein B-100 gene possessed any of the 4 mutations. Conclusion— The 4 missense mutations R46L, G106R, N157K, and R237W are associated with hypocholesterolemia and possibly increased response to statin therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Carriers of PCSK9 loss-of-function mutations have low LDL cholesterol and reduced risk of adverse cardiovascular events.
“Carriers of PCSK9 loss-of-function (LOF) mutations have low LDL cholesterol and reduced risk of adverse cardiovascular events (Cohen et al., 2005, 2006; Berge et al., 2006).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Berge et al., 2006
Cited by
Sorted by citations
Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol
Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1105803 · Cited by 664 · see citing works
Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials
Zhang, X.-L., Zhu, Q.-Q., Zhu, L., Chen, J.-Z., Chen, Q.-H., Li, G.-N., Xie, J., Kang, L.-N., & Xu, B. (2015) · BMC Medicine · doi:10.1186/s12916-015-0358-8 · Cited by 260 · see citing works
Resistance and intolerance to statins
Reiner, Ž. (2014) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2014.05.009 · Cited by 225 · see citing works
Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187 · see citing works
Lipid lowering therapy and circulating PCSK9 concentration
Nozue, T. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17012 · Cited by 127 · see citing works
Ni, Y. G., Condra, J. H., Orsatti, L., Shen, X., Di Marco, S., Pandit, S., Bottomley, M. J., Ruggeri, L., Cummings, R. T., Cubbon, R. M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.113035 · Cited by 107 · see citing works
Pisciotta, L., Bellocchio, A., & Bertolini, S. (2012) · Lipids in Health and Disease · doi:10.1186/1476-511x-11-123 · Cited by 79 · see citing works
Abboud, S., Karhunen, P. J., Lütjohann, D., Goebeler, S., Luoto, T., Friedrichs, S., Lehtimaki, T., Pandolfo, M., & Laaksonen, R. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001043 · Cited by 77 · see citing works
PCSK9 deficiency alters brain lipid composition without affecting brain development and function
Pärn, A., Olsen, D., Tuvikene, J., Kaas, M., Borisova, E., Bilgin, M., Elhauge, M., Vilstrup, J., Madsen, P., Ambrozkiewicz, M. C., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1084633 · Cited by 16 · see citing works
- Authors
- Berge, K. E., Ose, L., & Leren, T. P.
- Affiliations
- Oslo University Hospital (NO)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2006-05
- Volume
- 26
- Issue
- 5
- Pages
- 1094-1100
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2027196973
- Cited by
- 236
- References
- 0
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 7 · 2017: 14 · 2016: 11 · 2015: 15 · 2014: 20 · 2013: 12 · 2012: 15
- FWCI
- 21.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (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, missense mutations, hypocholesterolemia, statin response, familial hypercholesterolemia, LDL receptor degradation, proprotein convertases, hypercholesterolemia
- MeSH terms
- Proprotein Convertase 9, Adult, Alleles, Female, Haplotypes, Humans, Cholesterol, LDL, Male, Middle Aged, Receptors, LDL, Serine Endopeptidases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mutation, Missense, Proprotein Convertases, Dyslipidemias
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
