A Genome-Wide Association Study of Survival in Patients with Sepsis
Authors: Hernandez-Beeftink Tamara , Guillen-Guio Beatriz , Lorenzo-Salazar Jose M. , Corrales Almudena , Suarez-Pajes Eva , Feng Rui , Rubio-Rodríguez Luis A. , Paynton Megan L , Cruz-Guerrero Raquel , García-Laorden M. Isabel , Prieto-González Miryam , Rodríguez-Pérez Aurelio , Carriedo Demetrio , Blanco Jesús , Ambrós Alfonso , González-Higueras Elena , Espinosa Elena , Muriel Arturo , Tamayo Eduardo , Martin María M , Lorente Leonardo , Domínguez David , de Lorenzo Abelardo García , Giannini Heather M. , Reilly John P. , Jones Tiffanie K. , Añón José M. , Soro Marina , Carracedo Ángel , Wain Louise V. , Meyer Nuala J , Villar Jesús , Flores Carlos ,   the Genetics of Sepsis (GEN-SEP) Network
Published: May 2022

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 (ICUs). 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 (1,362 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 and functional annotations were evaluated on the identified genes and variants.

Findings

We identified three independent 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 mediator of the inflammatory response to tissue injury that is overexpressed in peripheral blood of non-surviving sepsis patients compared to those surviving (p=2.18×10−3).

Interpretation

We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Our findings could allow the identification of novel targets for sepsis treatment and patient risk stratification.

Research in context

Evidence before this study

Sepsis is defined as a life-threatening clinical syndrome of physiological, pathological, and biochemical abnormalities caused by a dysregulated host response to an infection, and with long-term physical, psychological, and cognitive disabilities. Many genetic studies have focused on identifying genetic risk factors associated with sepsis development and severity, but only four genome-wide association studies (GWAS) have been published to date. Three of them focused on sepsis mortality. The first study identified that common genetic variation in the FER gene associated with a reduced risk of death. The second study found variants associated with an increased risk of death in VPS13A, which is key in autophagic degradation. In the last study, variants of the CISH gene, involved in cytokine regulation, were associated with the risk of death. Nevertheless, there is a lack of GWAS focused on sepsis survival, which takes into account the probability estimates of death for each patient over time.

Added value of this study

To the best of our knowledge, we provide the results of the first GWAS of 28-day sepsis survival conducted to date. In this two-staged study, we identified three novel loci associated with reduced 28-day survival among sepsis patients. We identified one missense variant in SAMD9, which encodes a critical regulator in the inflammatory response and apoptosis. A significant upregulation of SAMD9 gene expression in whole blood was observed among non-surviving sepsis patients compared to those surviving. Associations were also found for one intergenic variant to SLC5A12\FIBIN and an intergenic variant to two non-coding RNAs (LINC00378\MIR3169).

Implications of all the available evidence

The identification of effective prognostic genetic markers in sepsis is a promising instrument for clinical practice. This study identified three novel genetic factors of fatal outcomes, all having interesting and important biological plausibly that could serve as novel targets for sepsis treatment. This knowledge is important to propose effective sepsis treatments and will be central in the development of personalized medicine approaches.