Dataset Information

Genetic variants associated with sepsis.

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.

SUBMITTER: Engoren M

PROVIDER: S-EPMC8916629 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Genetic variants associated with sepsis.

Engoren Milo M Jewell Elizabeth S ES Douville Nicholas N Moser Stephanie S Maile Michael D MD Bauer Melissa E ME

PloS one 20220311 3

<h4>Background</h4>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.<h4>Methods</h4>We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10-6 in p ...[more]

PMID: 35275946

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Project description:BackgroundKidney dysfunction is a common complication in septic patients. Studies have identified numerous risk factors for sepsis-associated acute kidney injury (S-AKI), yet there is wide variability in the incidence even among patients with similar risk factors, suggesting the presence of additional uncharacterized risk factors, including genetic differences. The expansion of biobanks, advances in genotyping, and standardized diagnostic criteria have enabled large-scale, hypothesis-generating studies into the genetic mechanisms underlying S-AKI. We hypothesize that the genetic pathway behind S-AKI has overlapping mechanisms with key differences based upon the specific subtype of acute kidney injury (AKI).MethodsTo test this hypothesis, we performed a genome-wide association study (GWAS) of S-AKI in three logistic regression models. Model 1, controlled for 1) age, 2) sex, 3) genotyping chip, and 4) the first five principal components. In Model 2, pre-sepsis baseline serum creatinine was added to the variables in Model 1. Finally, in Model 3, we controlled for the full range of patient, clinical, and ICU-related risk factors. Each of the 3-models were repeated in a pre-specified sensitivity analysis of higher severity S-AKI, defined as KDIGO Stage 2 or 3. We then compare associated variants and genes from our GWAS with previously published AKI sub-types and model other factors associated with S-AKI in our dataset.Findings3,348 qualifying Sepsis-3 patients have been genotyped in our dataset. Of these patients, 383 (11.4%) developed Stage 1, 2, or 3 AKI (primary outcome) and 181 (5.4%) developed Stage 2 or 3 AKI (sensitivity analysis). The median age was 61 years (interquartile range (IQR): 51,69), 42% were female, and the increase in SOFA score (between 48-hours before to 24-hours after the onset of suspected infection) was 2 (2-3). No variants exceeded our threshold for genome-wide significance (P<5x10-8), however, a total of 13 variants exceeded the suggestive (P<1x10-6) threshold. Notably, rs184516290 (chr1:199814965:G:A), near the NR5A2 gene, chr1:199805801:T:TA, also near the NR5A2 gene, and rs117313146 (chr15:31999784:G:C), near the CHRNA7 gene, were associated with S-AKI at the suggestive level in all three models presented. Variants in the suppressor of fused homolog (SUFU) gene, previously shown to be correlated with renal function in bacteremic patients, consistently exceeded the P<0.05 threshold in our models.ConclusionsWhile failing to identify any novel association for S-AKI at the level of genome-wide significance, our study did suggest multiple variants in previously characterized pathways for S-AKI including CHRNA7, NR5A2, and SUFU. We failed to replicate associations from multiple prior studies which may result from differences in how the phenotype was defined or, alternatively, limited genetic contribution and low heritability.

Project description:BACKGROUND: Toll like receptors (TLRs) signaling pathways, including the adaptor protein Mal encoded by the TIRAP gene, play a central role in the development of acute lung injury (ALI). Recently, the TIRAP variants have been described association with susceptibility to inflammatory diseases. The aim of this study was to investigate whether genetic variants in TIRAP are associated with the development of ALI. METHODS: A case-control collection from Han Chinese of 298 healthy subjects, 278 sepsis-associated ALI and 288 sepsis alone patients were included. Three tag single nucleotide polymorphisms (SNPs) of the TIRAP gene and two additional SNPs that have previously showed association with susceptibility to other inflammatory diseases were genotyped by direct sequencing. The differences of allele, genotype and haplotype frequencies were evaluated between three groups. RESULTS: The minor allele frequencies of both rs595209 and rs8177375 were significantly increased in ALI patients compared with both healthy subjects (odds ratio (OR) = 1.47, 95% confidence interval (CI):1.15-1.88, P = 0.0027 and OR = 1.97, 95% CI: (1.38-2.80), P = 0.0001, respectively) and sepsis alone patients (OR = 1.44, 95% CI: 1.12-1.85, P = 0.0041 and OR = 1.82, 95% CI: 1.28-2.57, P = 0.00079, respectively). Haplotype consisting of these two associated SNPs strengthened the association with ALI susceptibility. The frequency of haplotype AG (rs595209A, rs8177375G) in the ALI samples was significantly higher than that in the healthy control group (OR = 2.13, 95% CI: 1.46-3.09, P = 0.00006) and the sepsis alone group (OR = 2.24, 95% CI: 1.52-3.29, P = 0.00003). Carriers of the haplotype CA (rs595209C, rs8177375A) had a lower risk for ALI compared with healthy control group (OR = 0.69, 95% CI: 0.54-0.88, P = 0.0003) and sepsis alone group (OR = 0.71, 95% CI: 0.55-0.91, P = 0.0006). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. CONCLUSIONS: These results indicated that genetic variants in the TIRAP gene might be associated with susceptibility to sepsis-associated ALI in Han Chinese population. However, the association needs to be replicated in independent studies.

Dataset Information

Genetic variants associated with sepsis.

Background

Methods

Findings

Conclusions

Publications

Genetic variants associated with sepsis.

Similar Datasets

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