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Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors

Genga, Kelly Roveran ; Lo, Cody ; Cirstea, Mihai S. ; Leitao Filho, Fernando Sergio ; Walley, Keith R. ; Russell, James A. ; Linder, Adam LU ; Francis, Gordon A. and Boyd, John H. (2018) In EBioMedicine 38. p.257-264
Abstract

Background: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense... (More)

Background: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings: In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation: The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding: Canadian Institutes of Health Research (PJT-156056).

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mortality, PCSK9, Readmission, Sepsis, Septic shock
in
EBioMedicine
volume
38
pages
257 - 264
publisher
Elsevier
external identifiers
  • pmid:30473376
  • scopus:85057040731
ISSN
2352-3964
DOI
10.1016/j.ebiom.2018.11.032
language
English
LU publication?
yes
id
18b3de5a-128b-4e54-a74a-771233e83f30
date added to LUP
2018-12-04 13:42:54
date last changed
2020-03-24 06:32:26
@article{18b3de5a-128b-4e54-a74a-771233e83f30,
  abstract     = {<p>Background: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings: In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation: The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding: Canadian Institutes of Health Research (PJT-156056).</p>},
  author       = {Genga, Kelly Roveran and Lo, Cody and Cirstea, Mihai S. and Leitao Filho, Fernando Sergio and Walley, Keith R. and Russell, James A. and Linder, Adam and Francis, Gordon A. and Boyd, John H.},
  issn         = {2352-3964},
  language     = {eng},
  pages        = {257--264},
  publisher    = {Elsevier},
  series       = {EBioMedicine},
  title        = {Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors},
  url          = {http://dx.doi.org/10.1016/j.ebiom.2018.11.032},
  doi          = {10.1016/j.ebiom.2018.11.032},
  volume       = {38},
  year         = {2018},
}