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Epigenome-wide DNA methylation profiling in septic and non-septic patients with similar infections: Potential use as sepsis biomarkers

ABSTRACT: Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, leading to organ failure. Despite its significant global burden, the underlying mechanisms of immune dysfunction in sepsis remain incompletely understood. This study explores the role of DNA methylation in white blood cells in sepsis pathogenesis by assessing a prospective case-control study comparing DNA methylation profiles between patients with community-acquired sepsis and matched controls with similar infections who did not develop sepsis. Blood samples were collected within 24 hours of hospital admission, and DNA methylation was analyzed using Illumina MethylationEPIC 850 v2 arrays and bisulfite pyrosequencing. The discovery cohort (n=32) identified 4,640 differentially methylated positions (DMPs), with notable hypomethylation in immune-related genes. Functional enrichment analysis revealed significant involvement of these genes in immune processes, including neutrophil activation and monocyte differentiation. Key findings highlighted hypomethylation of SERPINA1, AZU1, MPO, and SLX4, which was validated in an independent cohort (n=28). Correlation analyses demonstrated significant associations between the methylation levels of these genes and clinical severity markers, such as SOFA score and procalcitonin levels. Notably, SLX4 hypomethylation showed the highest predictive value for poor prognosis (AUC 0.821), while SERPINA1 hypomethylation exhibited strong diagnostic potential for sepsis (AUC 0.858). Our findings suggest that DNA methylation changes, particularly in immune-related genes, could serve as valuable biomarkers for diagnosing sepsis and predicting patient outcomes. Further research is warranted to confirm their clinical utility and explore potential therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285813 | GEO | 2025/01/24

REPOSITORIES: GEO

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Project description:Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1,169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranked regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (p=0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR=1.061, 95% CI: 1.032-1.090), and the sensitivity (AUC = 0.638, 95% CI: 0.586-0.690), (Males=0.675, Females=0.609), was better than of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals that stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM, and suggest a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM. Five pools of DNA samples consist of 710 T2DM patients and 459 control individuals were analyzed for average methylation levels at 1,461,753 DNA genomic fragments containing 3,359,645 CpG methylation sites using four SNP arrays for each sample, two 'genomic' (before treatment) replicates and two MSRE (treatment with a cocktail of five methyl-sensitive-restriction-enzyme) replicates. The analysis was done using the Affymetrix SNP 6.0 array.

Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.

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Epigenome-wide DNA methylation profiling in septic and non-septic patients with similar infections: Potential use as sepsis biomarkers

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