Genetic Predisposition to the Mortality in Septic Shock Patients: From GWAS to the Identification of a Regulatory Variant Modulating the Activity of a CISH Enhancer

Rosier, Florian; Dupuis, Claire; Baaklini, Sabrina; Puthier, Denis; Brun, Catherine; Pradel, Lydie; Rihet, Pascal; Payen, Didier

doi:10.3390/ijms22115852

Cited by 18 publications

(15 citation statements)

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“…Variants were prioritized for the next stage if they satisfied having the same effect direction, a p<0.05 in both GEN-SEP recruitment periods, and a p<5.0x10 -7 after the meta-analysis of both periods. Association results of this first stage were also inspected to evaluate whether the variants or genes previously associated with sepsis mortality by other studies were also associated in GEN-SEP [15][16][17] .…”

Section: Genotyping and Statistical Analysesmentioning

confidence: 99%

“…However, the number of GWAS of sepsis or its complications is limited. To date, only three GWAS have been completed for sepsis mortality, although the likelihood of death for each patient over time was not considered [15][16][17] . Specifically, Rautanen et al 15 analysed 28-day mortality in patients with pneumonia, linking the FER tyrosine kinase (FER) gene variation with reduced risk for death from sepsis.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Genome-Wide Association Study of Survival in Patients with Sepsis

Hernández-Beeftink

Guillén‐Guío

Lorenzo-Salazar

et al. 2022

Preprint

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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 (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.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 (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.FindingsWe 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).InterpretationWe 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 contextEvidence before this studySepsis 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 studyTo 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 evidenceThe 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.

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Section: Genotyping and Statistical Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Genome-Wide Association Study of Survival in Patients with Sepsis

Hernández-Beeftink

Guillén‐Guío

Lorenzo-Salazar

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Additionally, Scherag and colleagues found that the top ranking variants associated with 28-day mortality from sepsis in their study were located in the Vacuolar Protein Sorting 13 Homolog A ( VPS13A ) gene [ 16 ]. Rosier and colleagues identified variants within the Cytokine Inducible SH2 Containing Protein ( CISH ) gene associated with mortality due to septic shock at day 7 or day 28 [ 17 ]. Finally, D’Urso and colleagues performed a GWAS of susceptibility and mortality in septic shock and polygenic risk score (PRS) analysis to assess the genetic overlap between septic shock risk/mortality with clinically relevant traits.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide association study of survival in patients with sepsis

et al. 2022

View full text Add to dashboard Cite

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.

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“…Inflammation is influenced by genetic susceptibility. Inflammatory cytokine genes polymorphisms have been subject of study trying to explain the etiology of gynecological (leiomyomas) [12,13] and non-gynecological pathologies [14][15][16]. Although the contribution of genetics is well supported by many studies, they have not provided a simple and unambiguous answer to the etiology of endometriosis [17,18].…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of TNF-alpha (− 308), IL-1beta (+ 3954) and IL1-Ra (VNTR) are associated to severe stage of endometriosis in Mexican women: a case control study

et al. 2022

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Background Endometriosis is an estrogen-dependent and chronic inflammatory disease affecting up to 10% of women. It is the result of a combined interaction of genetic, epigenetic, environmental, lifestyle, reproductive and local inflammatory factors. In this study, we investigated whether single nucleotide polymorphisms (SNPs) mapping to TNF-alpha (TNF, rs1800629) and IL-1beta (IL1B, rs1143634) and variable number tandem repeat polymorphism mapping to IL1-Ra (IL1RN intron 2, rs2234663) genetic loci are associated with risk for endometriosis in a Mexican mestizo population. Methods This study included 183 women with confirmed endometriosis (ENDO) diagnosed after surgical laparoscopy and 186 women with satisfied parity and without endometriosis as controls (CTR). PCR/RFLP technique was used for genotyping SNPs (rs1800629 and rs1143634); PCR for genotyping rs2234663. Results We found no statistical differences in age between groups nor among stages of endometriosis and the CTR group. We observed no difference in genotype and allele frequencies, nor carriage rate between groups in none of the three studied polymorphisms. The prevalence of TNF*2-allele heterozygotes (p = 0.025; OR 3.8), TNF*2-allele (p = 0.029; OR 3.4), IL1B*2-allele heterozygotes (p = 0.044; OR 2.69) and its carriage rate (p = 0.041; OR 2.64) in endometriosis stage IV was higher than the CTR group. Surprisingly, the carriage rate of IL1RN*2-allele (ENDO: p = 0.0004; OR 0.4; stage I: p = 0.002, OR 0.38; stage II: p = 0.002, OR 0.35; stage III: p = 0.003, OR 0.33), as well as the IL1RN*2-allele frequencies (ENDO: p = 0.0008, OR 0.55; I: p = 0.037, OR 0.60; II: p = 0.002, OR 0.41; III: p = 0.003, OR 0.38) were lower than the CTR group. Women with endometriosis stage IV (severe) had frequencies more alike to the CTR group in the IL1RN*2 allele frequency (31.2% vs. 27.2%) and carriage rate (37.5% vs. 41.9%). Conclusion Although these polymorphisms are not associated with the risk of endometriosis, Mexican mestizo women with severe stage of endometriosis have higher frequencies of TNF*2-, IL1B*2- and IL1RN*2-alleles, which may explain a possible correlation with disease severity rather than predisposition or risk.

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Genetic Predisposition to the Mortality in Septic Shock Patients: From GWAS to the Identification of a Regulatory Variant Modulating the Activity of a CISH Enhancer

Cited by 18 publications

References 77 publications

A Genome-Wide Association Study of Survival in Patients with Sepsis

A Genome-Wide Association Study of Survival in Patients with Sepsis

A genome-wide association study of survival in patients with sepsis

Polymorphisms of TNF-alpha (− 308), IL-1beta (+ 3954) and IL1-Ra (VNTR) are associated to severe stage of endometriosis in Mexican women: a case control study

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