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PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort

BACKGROUND: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. METHODS: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the...

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Autores principales: Small, Aeron M., Huffman, Jennifer E., Klarin, Derek, Lynch, Julie A., Assimes, Themistocles, DuVall, Scott, Sun, Yan V., Shere, Labiba, Natarajan, Pradeep, Gaziano, Michael, Rader, Daniel J., Wilson, Peter W. F., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Casas, Juan P., Damrauer, Scott M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652310/
https://www.ncbi.nlm.nih.gov/pubmed/33166319
http://dx.doi.org/10.1371/journal.pone.0239752
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author Small, Aeron M.
Huffman, Jennifer E.
Klarin, Derek
Lynch, Julie A.
Assimes, Themistocles
DuVall, Scott
Sun, Yan V.
Shere, Labiba
Natarajan, Pradeep
Gaziano, Michael
Rader, Daniel J.
Wilson, Peter W. F.
Tsao, Philip S.
Chang, Kyong-Mi
Cho, Kelly
O’Donnell, Christopher J.
Casas, Juan P.
Damrauer, Scott M.
author_facet Small, Aeron M.
Huffman, Jennifer E.
Klarin, Derek
Lynch, Julie A.
Assimes, Themistocles
DuVall, Scott
Sun, Yan V.
Shere, Labiba
Natarajan, Pradeep
Gaziano, Michael
Rader, Daniel J.
Wilson, Peter W. F.
Tsao, Philip S.
Chang, Kyong-Mi
Cho, Kelly
O’Donnell, Christopher J.
Casas, Juan P.
Damrauer, Scott M.
author_sort Small, Aeron M.
collection PubMed
description BACKGROUND: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. METHODS: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. RESULTS: Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80–0.87], p = 6.0 x 10(−21); AAA OR 0.76 [95% CI 0.68–0.86], p = 2.9 x 10(−06)). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71–0.97], p = 2.3 x 10(−04)) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78–0.93], p = 5.0 x 10(−04)). CONCLUSIONS: Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
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spelling pubmed-76523102020-11-18 PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort Small, Aeron M. Huffman, Jennifer E. Klarin, Derek Lynch, Julie A. Assimes, Themistocles DuVall, Scott Sun, Yan V. Shere, Labiba Natarajan, Pradeep Gaziano, Michael Rader, Daniel J. Wilson, Peter W. F. Tsao, Philip S. Chang, Kyong-Mi Cho, Kelly O’Donnell, Christopher J. Casas, Juan P. Damrauer, Scott M. PLoS One Research Article BACKGROUND: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. METHODS: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. RESULTS: Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80–0.87], p = 6.0 x 10(−21); AAA OR 0.76 [95% CI 0.68–0.86], p = 2.9 x 10(−06)). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71–0.97], p = 2.3 x 10(−04)) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78–0.93], p = 5.0 x 10(−04)). CONCLUSIONS: Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning. Public Library of Science 2020-11-09 /pmc/articles/PMC7652310/ /pubmed/33166319 http://dx.doi.org/10.1371/journal.pone.0239752 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Small, Aeron M.
Huffman, Jennifer E.
Klarin, Derek
Lynch, Julie A.
Assimes, Themistocles
DuVall, Scott
Sun, Yan V.
Shere, Labiba
Natarajan, Pradeep
Gaziano, Michael
Rader, Daniel J.
Wilson, Peter W. F.
Tsao, Philip S.
Chang, Kyong-Mi
Cho, Kelly
O’Donnell, Christopher J.
Casas, Juan P.
Damrauer, Scott M.
PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title_full PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title_fullStr PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title_full_unstemmed PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title_short PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
title_sort pcsk9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652310/
https://www.ncbi.nlm.nih.gov/pubmed/33166319
http://dx.doi.org/10.1371/journal.pone.0239752
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