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Title: A genome-wide association study of survival in patients with sepsis
Authors: Hernandez-Beeftink, Tamara
Guillen-Guio, Beatriz
Lorenzo-Salazar, José M.
Corrales, Almudena
Suárez-Pajes, Eva
Feng, Rui
Rubio-Rodríguez, Luis A.
Paynton, Megan L.
Cruz, Raquel
García-Laorden, M. Isabel
Prieto-González, Miryam
Rodríguez Pérez, Aurelio Eduardo 
Carriedo, Demetrio
Blanco, Jesús
Ambrós, Alfonso
González-Higueras, Elena
Espinosa, Elena
Muriel, Arturo
Tamayo, Eduardo
Martin, María M.
Lorente, Leonardo
Dominguez, David
García de Lorenzo, Abelardo
Giannini, Heather M.
Reilly, John P.
Jones, Tiffanie K.
Añón, José M.
Soro, Marina
Carracedo, Ángel
Wain, Louise V.
Meyer, Nuala J.
Villar, Jesús
Hernández Flores, Carmen Nieves 
UNESCO Clasification: 32 Ciencias médicas
3201 Ciencias clínicas
320102 Genética clínica
Keywords: Sepsis
Genome-wide association study
28 days
Issue Date: 2022
Journal: Critical Care 
Abstract: Background: Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. Methods: This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10−8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. Findings: We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37–6.78], p = 4.92 × 10−8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. Interpretation: We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.
ISSN: 1364-8535
DOI: 10.1186/s13054-022-04208-5
Source: Critical Care [ISSN 1364-8535], v. 26, 341, (2022)
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