Low Low-Density Lipoprotein Levels Are Associated With, But Do Not Causally Contribute to, Increased Mortality in Sepsis

Objectives: Low low-density lipoprotein levels are associated with increased mortality in sepsis. Whether low low-density lipoprotein levels contribute causally to adverse sepsis outcome is unknown. Design: Retrospective analysis of two sepsis patient cohorts using a Mendelian Randomization strategy. Setting: Sepsis patients enrolled into clinical research cohorts at tertiary care teaching hospitals. Patients: The first cohort included 200 sepsis patients enrolled in an observational study in a hospital Emergency Department. The second cohort included genotyped patients enrolled in the Vasopressin and Septic Shock Trial. Interventions: Retrospective analysis of these patient datasets. In 632 patients enrolled in Vasopressin and Septic Shock Trial, Proprotein Convertase Subtilisin/Kexin type 9, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase single nucleotide polymorphisms known to be associated with low-density lipoprotein levels were genotyped, and a genetic score related to low-density lipoprotein levels was calculated. Measurements and Main Results: In the first cohort, we replicated the finding that low low-density lipoprotein levels are associated with increased 28-day mortality. In genotyped patients in the Vasopressin and Septic Shock Trial trial, we found that the 3-Hydroxy-3-Methylglutaryl-CoA Reductase genetic score, known to be directly related to low low-density lipoprotein levels, was not associated with increased mortality. Surprisingly the Proprotein Convertase Subtilisin/Kexin type 9 genetic score, known to be directly related to low low-density lipoprotein levels, was associated with decreased (not increased) mortality. Conclusions: Both 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Proprotein Convertase Subtilisin/Kexin type 9 genetic scores should have been associated with increased mortality if low low-density lipoprotein levels contributed causally to sepsis mortality. But this was not the case, and the opposite was observed for the Proprotein Convertase Subtilisin/Kexin type 9 genetic score. This suggests that low-density lipoprotein levels, per se, do not contribute causally to adverse sepsis outcomes. The Proprotein Convertase Subtilisin/Kexin type 9 genetic score finding raises the possibility that increased low-density lipoprotein clearance (the effect of these Proprotein Convertase Subtilisin/Kexin type 9 genotypes) may contribute to improved sepsis outcomes. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/29S62lw). Supported, in part, by the Canadian Institutes of Health Research FDN 154311. Dr. Walley is supported by the Canadian Institutes of Health Research (CIHR) FDN 154311. Dr. Boyd disclosed he is a Co-Founder of Cyon Therapeutics, a biotech company aiming to develop Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors for sepsis. Ms. Kong’s institution received funding from CIHR. Dr. Russell received funding from Asahi Kasei Pharma America (developing thrombomodulin in sepsis), consulting fees from Cubist Pharmaceuticals (now owned by Merck, formerly Trius Pharmaceuticals, developing antibiotics), Ferring Pharmaceuticals (which manufactures vasopressin and is developing selepressin), Grifols (which sells albumin), MedImmune (regarding sepsis), Leading Biosciences (developing a sepsis therapeutic), La Jolla Pharmaceuticals (developing a sepsis therapeutic), CytoVale (developing a sepsis diagnostic), Asahi Kesai (developing a sepsis therapeutic), Sirius Genomics (now closed, formerly involved in pharmacogenomics research in sepsis), and received grant support from Sirius Genomics and Ferring Pharmaceuticals that was provided to and administered by University of British Columbia (UBC). Drs. Walley, Boyd, and Russell report being inventors on patents owned by the UBC that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. For information regarding this article, E-mail: Keith.Walley@hli.ubc.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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