• Tamara Hernandez-Beeftink, Beatriz Guillen-Guio, Jose M Lorenzo-Salazar, Almudena Corrales, Eva Suarez-Pajes, Rui Feng, Luis A Rubio-Rodríguez, Megan L Paynton, Raquel Cruz, M Isabel García-Laorden, Miryam Prieto-González, Aurelio Rodríguez-Pérez, Demetrio Carriedo, Jesús Blanco, Alfonso Ambrós, Elena González-Higueras, Elena Espinosa, Arturo Muriel, Eduardo Tamayo, María M Martin, Leonardo Lorente, David Domínguez, de LorenzoAbelardo GarcíaAGIntensive Care Unit, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain., Heather M Giannini, John P Reilly, Tiffanie K Jones, José M Añón, Marina Soro, Ángel Carracedo, Louise V Wain, Nuala J Meyer, Jesús Villar, Carlos Flores, and Genetics of Sepsis (GEN-SEP) Network.
• Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario S/N, Santa Cruz de Tenerife, Spain.
• Crit Care. 2022 Nov 5; 26 (1): 341341.

BackgroundSepsis 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.MethodsThis 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.FindingsWe 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.InterpretationWe 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.© 2022. The Author(s).

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