Polygenic Risk Score for Early Prediction of Sepsis Risk in the Polytrauma Screening Cohort

Lu, Hongxiang; Wen, Dalin; Sun, Jianhui; Du, Juan; Qiao, Liang; Zhang, Huacai; Zhang, Lianyang; Jiang, Jianxin; Zhang, Anqiang

doi:10.3389/fgene.2020.545564

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…In a study of Han Chinese trauma patients, Lu et al studied 64 genetic variants and found 4 to be associated with sepsis-2: NOS2, PPARG, HSPA12A, and TLR1 [49]. We found PPARG to be associated with only Sepsis-2, similar to their study, giving credence to its association.…”

Section: Plos Onesupporting

confidence: 85%

Genetic variants associated with sepsis

et al. 2022

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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.

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Section: Plos Onesupporting

confidence: 85%

Genetic variants associated with sepsis

et al. 2022

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“…The larger MDA indicates the greater importance of the variable. In this study, those variables with MDA larger than 1 were considered as important transcriptomic features for vitiligo ( Lu et al, 2020 ; Monforte et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Development of a Multi-Target Strategy for the Treatment of Vitiligo via Machine Learning and Network Analysis Methods

et al. 2021

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Vitiligo is a complex disorder characterized by the loss of pigment in the skin. The current therapeutic strategies are limited. The identification of novel drug targets and candidates is highly challenging for vitiligo. Here we proposed a systematic framework to discover potential therapeutic targets, and further explore the underlying mechanism of kaempferide, one of major ingredients from Vernonia anthelmintica (L.) willd, for vitiligo. By collecting transcriptome and protein-protein interactome data, the combination of random forest (RF) and greedy articulation points removal (GAPR) methods was used to discover potential therapeutic targets for vitiligo. The results showed that the RF model performed well with AUC (area under the receiver operating characteristic curve) = 0.926, and led to prioritization of 722 important transcriptomic features. Then, network analysis revealed that 44 articulation proteins in vitiligo network were considered as potential therapeutic targets by the GAPR method. Finally, through integrating the above results and proteomic profiling of kaempferide, the multi-target strategy for vitiligo was dissected, including 1) the suppression of the p38 MAPK signaling pathway by inhibiting CDK1 and PBK, and 2) the modulation of cellular redox homeostasis, especially the TXN and GSH antioxidant systems, for the purpose of melanogenesis. Meanwhile, this strategy may offer a novel perspective to discover drug candidates for vitiligo. Thus, the framework would be a useful tool to discover potential therapeutic strategies and drug candidates for complex diseases.

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“…For sepsis, a single variant inadequately reflects the overall risk, but partial susceptibility may be captured when pooling a suite of genetic alleles, rendering the application of PRSs possible. Lu et al extracted 17 variants from 64 candidate loci to construct a weighted genetic risk score, which was confirmed to be positively correlated with traumatic sepsis morbidity and fitted better when the injury severity score was added ( 147 ). Similarly, another PRSs program showed a good performance in screening out high-risk individuals ( 148 ).…”

Section: Precision Medicine In Neonatal Sepsismentioning

confidence: 99%

A narrative review of precision medicine in neonatal sepsis: genetic and epigenetic factors associated with disease susceptibility

Dai¹,

Zhou²

2023

Transl Pediatr

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Background and Objective: Neonatal sepsis is a dysregulated host response to an infectious agent that results in severe morbidity and mortality among neonates worldwide. Given the complex and heterogenous nature of neonatal sepsis, early diagnosis and individualized treatment remain challenges for clinicians despite clinical advance. Epidemiological studies on twins suggest that hereditary factors act in conjunction with environmental factors to affect neonatal sepsis susceptibility. However, little is known about hereditary risks at present. This review aims to elucidate neonatal hereditary predisposition to sepsis and outline thoroughly the genomic landscape underlying neonatal sepsis, which may, to a large extent, facilitate precision medicine in this area.Methods: PubMed was searched for all published literature relating to neonatal sepsis using Medical Subject Headings (MeSH) terms, with a focus on hereditary factors. Without any restriction on article type, articles published in English prior to June 1, 2022, were retrieved. Additionally, pediatric, adult, and animaland laboratory-based studies were reviewed wherever possible.

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Polygenic Risk Score for Early Prediction of Sepsis Risk in the Polytrauma Screening Cohort

Cited by 5 publications

References 38 publications

Genetic variants associated with sepsis

Genetic variants associated with sepsis

Development of a Multi-Target Strategy for the Treatment of Vitiligo via Machine Learning and Network Analysis Methods

A narrative review of precision medicine in neonatal sepsis: genetic and epigenetic factors associated with disease susceptibility

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