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PCSK9 Loss-of-Function (LOF) Genotype Is Associated with Decreased Readmission or Death in Sepsis Associated with Shock and/or Pulmonary Dysfunction
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A4175 - PCSK9 Loss-of-Function (LOF) Genotype Is Associated with Decreased Readmission or Death in Sepsis Associated with Shock and/or Pulmonary Dysfunction
Author Block: K. Roveran Genga1, C. Lo1, M. Cirstea2, H. Kong1, A. K. Leung1, T. Shimada1, K. R. Walley1, J. A. Russell1, A. Linder3, J. H. Boyd1; 1Centre for Heart and Lung Innovation - St. Paul's Hospital - University of British Columbia, Vancouver, BC, Canada, 2Faculty of Science - Microbiology and Immunology, Vancouver, BC, Canada, 3Division of Infection Medicine - Lund University, Lund, Sweden.
Rationale: Reduced activity of Proprotein Convertase Subtilisin/kexin type 9 (PCSK9) increases low density lipoprotein (LDL) receptor density on hepatocytes, which reduces the inflammatory response to sepsis due to increased clearance of pathogen lipids incorporated into LDL. The purpose of this study was to determine whether there is an association of PCSK9 Loss-of-Function (LOF) variants and the risk of death and unplanned infection-related hospital readmission(s) (IRR) within one year following an episode of sepsis.
Methods: This was a retrospective observational study. 633 patients admitted for sepsis at St. Paul’s Hospital in Vancouver (BC, Canada) from two similar cohorts were included (Cohort 1: patients admitted between 2004 and 2009, n=448; Cohort 2: patients admitted between 2011 and 2015, n=185). All patients were genotyped for R46L, A53V, and I474V PCSK9 missense PCSK9 LOF SNPs and were classified into 3 groups according to the number of LOF alleles: WT (0 LOF), 1 LOF, and 2 or more LOFs. The association of PCSK9 LOF genotype with the primary outcome, composite 1-year mortality and IRR, was evaluated using the Log-rank test and Cox-regression proportional hazards models.
Results: 351 patients were classified as WT (55.5%), 197 (31.1%) had 1 LOF allele, and 85 (13.4%) had 2 or more LOF alleles. Baseline characteristics were similar among groups. Time to event analysis showed no significant differences among groups (p=0.145). However, in a subgroup analysis of patients who required vasopressors and/or ventilatory support during hospitalization (n=453), time to composite outcome was significantly longer among patients with 2 or more PCSK9 LOF alleles (p=0.037). The most significant difference was observed between WT and 2 or more LOF group (p=0.021), whereas there was a trend towards a statistically significant difference between 1 LOF and 2 or more LOF groups (p=0.053). In the Cox regression analysis, the presence of 2 or more LOF alleles was an independent predictor of lower risk of death or IRR within 1 year (HR=0.631, 95% CI=0.404-0.984, p=0.042).
Conclusion: PCSK9 LOF genotype is associated with a significantly lower risk of death or unplanned infection related readmission within 1 year in patients with sepsis associated with shock and/or pulmonary dysfunction. Evaluation of PCSK9 inhibition to prevent death or readmission is warranted.
Author Block: K. Roveran Genga1, C. Lo1, M. Cirstea2, H. Kong1, A. K. Leung1, T. Shimada1, K. R. Walley1, J. A. Russell1, A. Linder3, J. H. Boyd1; 1Centre for Heart and Lung Innovation - St. Paul's Hospital - University of British Columbia, Vancouver, BC, Canada, 2Faculty of Science - Microbiology and Immunology, Vancouver, BC, Canada, 3Division of Infection Medicine - Lund University, Lund, Sweden.
Rationale: Reduced activity of Proprotein Convertase Subtilisin/kexin type 9 (PCSK9) increases low density lipoprotein (LDL) receptor density on hepatocytes, which reduces the inflammatory response to sepsis due to increased clearance of pathogen lipids incorporated into LDL. The purpose of this study was to determine whether there is an association of PCSK9 Loss-of-Function (LOF) variants and the risk of death and unplanned infection-related hospital readmission(s) (IRR) within one year following an episode of sepsis.
Methods: This was a retrospective observational study. 633 patients admitted for sepsis at St. Paul’s Hospital in Vancouver (BC, Canada) from two similar cohorts were included (Cohort 1: patients admitted between 2004 and 2009, n=448; Cohort 2: patients admitted between 2011 and 2015, n=185). All patients were genotyped for R46L, A53V, and I474V PCSK9 missense PCSK9 LOF SNPs and were classified into 3 groups according to the number of LOF alleles: WT (0 LOF), 1 LOF, and 2 or more LOFs. The association of PCSK9 LOF genotype with the primary outcome, composite 1-year mortality and IRR, was evaluated using the Log-rank test and Cox-regression proportional hazards models.
Results: 351 patients were classified as WT (55.5%), 197 (31.1%) had 1 LOF allele, and 85 (13.4%) had 2 or more LOF alleles. Baseline characteristics were similar among groups. Time to event analysis showed no significant differences among groups (p=0.145). However, in a subgroup analysis of patients who required vasopressors and/or ventilatory support during hospitalization (n=453), time to composite outcome was significantly longer among patients with 2 or more PCSK9 LOF alleles (p=0.037). The most significant difference was observed between WT and 2 or more LOF group (p=0.021), whereas there was a trend towards a statistically significant difference between 1 LOF and 2 or more LOF groups (p=0.053). In the Cox regression analysis, the presence of 2 or more LOF alleles was an independent predictor of lower risk of death or IRR within 1 year (HR=0.631, 95% CI=0.404-0.984, p=0.042).
Conclusion: PCSK9 LOF genotype is associated with a significantly lower risk of death or unplanned infection related readmission within 1 year in patients with sepsis associated with shock and/or pulmonary dysfunction. Evaluation of PCSK9 inhibition to prevent death or readmission is warranted.
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