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. 2022 Mar 11;17(3):e0265052.
doi: 10.1371/journal.pone.0265052. eCollection 2022.

Genetic variants associated with sepsis

Milo Engoren  1 , Elizabeth S Jewell  1 , Nicholas Douville  1 , Stephanie Moser  1 , Michael D Maile  1 , Melissa E Bauer  1   2
Affiliations

Genetic variants associated with sepsis

Milo Engoren et al. PLoS One. .

Abstract

Background: The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be used to create individual risk profile. The purpose of this study was to create a polygenic risk score and determine the genetic variants associated with sepsis.

Methods: We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10-6 in patients with Sepsis-2 or Sepsis-3. Genome-wide association was performed using Firth bias-corrected logistic regression. Semi-parsimonious logistic regression was used to create polygenic risk scores and reduced regression to determine the genetic variants independently associated with sepsis.

Findings: 2261 patients had sepsis and 13,068 control patients did not. The polygenic risk scores had good discrimination: c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3. We found 772 genetic variants associated with Sepsis-2 and 442 with Sepsis-3, p<0.01. After multivariate adjustment, 100 variants on 85 genes were associated with Sepsis-2 and 69 variants in 54 genes with Sepsis-3. Twenty-five variants were present in both the Sepsis-2 and Sepsis-3 groups out of 32 genes that were present in both groups. The other 7 genes had different variants present. Most variants had small effect sizes.

Conclusions: Sepsis-2 and Sepsis-3 have both separate and shared genetic variants. Most genetic variants have small effects sizes, but cumulatively, the polygenic risk scores have good discrimination.

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Conflict of interest statement

Nicholas Douville was supported by a Foundation for Anesthesia Education and Research (FAER) Mentored Research Training Grant Michael Maile was supported by the American Diabetes Association. Milo Engoren has received consulting fee from Aerogen and Masimo. The other authors have nothing to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Patient flowchart.
Fig 2
Fig 2. Venn Diagram showing the number of patients with sepsis by Sepsis-2 (N = 2040) or Sepsis-3 (N = 1295) criteria or both (N = 1074) and the numbers of genes and genetic variants associated with each sepsis phenotype.
Fig 3
Fig 3. Manhattan plot showing the single nucleotide polymorphisms and their univariate p-values for Sepsis-2.
Fig 4
Fig 4. Manhattan plot showing the single nucleotide polymorphisms and their univariate p-values for Sepsis-3.
Fig 5
Fig 5. Calibration plot showing the fraction of patients with sepsis for each decile of risk calculated from the polygenic risk score.
Sepsis-2 (left), Sepsis-3 (right).
See this image and copyright information in PMC

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