A Genetic Approach to the Association Between PCSK9 and Sepsis

JAMA Netw Open. 2019 Sep 4;2(9):e1911130. doi: 10.1001/jamanetworkopen.2019.11130.


Importance: Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date.

Objective: To test the associations between PCSK9 genetic variants, a PCSK9 genetic risk score (GRS), or genetically estimated PCSK9 expression levels and the risk of sepsis among patients admitted to a hospital with infection.

Design, setting, and participants: This retrospective cohort study used deidentified electronic health records to identify patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, or the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from April 1, 2018, to March 16, 2019.

Exposures: Four known PCSK9 functional variants, a GRS for PCSK9, and genetically estimated PCSK9 expression.

Main outcomes and measures: The primary outcome was sepsis; secondary outcomes included cardiovascular failure and in-hospital death.

Results: Of patients with infection, genotype information was available in 10 922 white patients for PCSK9 functional variants (5628 men [51.5%]; mean [SD] age, 60.1 [15.7] years), including 7624 patients with PCSK9 GRS and 6033 patients with estimated PCSK9 expression. Of these, 3391 developed sepsis, 835 developed cardiovascular failure, and 366 died during hospitalization. None of the 4 functional PCSK9 variants were significantly associated with sepsis, cardiovascular failure, or in-hospital death, with or without adjustment for (1) age and sex or (2) age, sex, and Charlson-Deyo comorbidities (in model adjusted for age, sex, and comorbidities, odds ratios for any loss-of function variant were 0.96 [95% CI, 0.88-1.04] for sepsis, 1.05 [95% CI, 0.90-1.22] for cardiovascular failure, and 0.89 [95% CI, 0.72-1.11] for death). Similarly, neither the PCSK9 GRS nor genetically estimated PCSK9 expression were significantly associated with sepsis, cardiovascular failure, or in-hospital death in any of the analysis models. For GRS, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.96-1.06; P = .70), 1.03 for cardiovascular failure (95% CI, 0.95-1.12; P = .48), and 1.05 for in-hospital death (95% CI, 0.92-1.19; P = .50). For genetically estimated PCSK9 expression, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.95-1.06; P = .86), 0.96 for cardiovascular failure (95% CI, 0.88-1.05; P = .41), and 0.99 for in-hospital death (95% CI, 0.87-1.14; P = .94).

Conclusions and relevance: In this study, PCSK9 genetic variants were not significantly associated with risk of sepsis or the outcomes of sepsis in patients hospitalized with infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Hospital Mortality*
  • Hospitalization
  • Humans
  • Infections / epidemiology
  • Infections / therapy*
  • Male
  • Middle Aged
  • Odds Ratio
  • Proprotein Convertase 9 / genetics*
  • Renal Insufficiency / epidemiology
  • Respiration, Artificial
  • Respiratory Insufficiency / epidemiology
  • Respiratory Insufficiency / therapy
  • Retrospective Studies
  • Sepsis / epidemiology
  • Sepsis / genetics*
  • Shock / epidemiology
  • Shock / genetics*
  • Shock / therapy
  • Vasoconstrictor Agents / therapeutic use


  • Vasoconstrictor Agents
  • PCSK9 protein, human
  • Proprotein Convertase 9