PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.
<h4>Background</h4>Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.<h4>Methods</h4>We created a genetic risk score (GRS) for PCSK9 using four single nucleotid...
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doaj-6cee8e62b2a4445990cf5244b38c248f2021-05-12T04:31:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-011511e023975210.1371/journal.pone.0239752PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.Aeron M SmallJennifer E HuffmanDerek KlarinJulie A LynchThemistocles AssimesScott DuVallYan V SunLabiba SherePradeep NatarajanMichael GazianoDaniel J RaderPeter W F WilsonPhilip S TsaoKyong-Mi ChangKelly ChoChristopher J O'DonnellJuan P CasasScott M DamrauerVA Million Veteran Program<h4>Background</h4>Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.https://doi.org/10.1371/journal.pone.0239752 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aeron M Small Jennifer E Huffman Derek Klarin Julie A Lynch Themistocles Assimes Scott DuVall Yan V Sun Labiba Shere Pradeep Natarajan Michael Gaziano Daniel J Rader Peter W F Wilson Philip S Tsao Kyong-Mi Chang Kelly Cho Christopher J O'Donnell Juan P Casas Scott M Damrauer VA Million Veteran Program |
spellingShingle |
Aeron M Small Jennifer E Huffman Derek Klarin Julie A Lynch Themistocles Assimes Scott DuVall Yan V Sun Labiba Shere Pradeep Natarajan Michael Gaziano Daniel J Rader Peter W F Wilson Philip S Tsao Kyong-Mi Chang Kelly Cho Christopher J O'Donnell Juan P Casas Scott M Damrauer VA Million Veteran Program PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort. PLoS ONE |
author_facet |
Aeron M Small Jennifer E Huffman Derek Klarin Julie A Lynch Themistocles Assimes Scott DuVall Yan V Sun Labiba Shere Pradeep Natarajan Michael Gaziano Daniel J Rader Peter W F Wilson Philip S Tsao Kyong-Mi Chang Kelly Cho Christopher J O'Donnell Juan P Casas Scott M Damrauer VA Million Veteran Program |
author_sort |
Aeron M Small |
title |
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_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_sort |
pcsk9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2020-01-01 |
description |
<h4>Background</h4>Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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. |
url |
https://doi.org/10.1371/journal.pone.0239752 |
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