Evidence map›Paper›PMID 41076474›Full record

ArticlePediatric research2026

Deleterious variants in LTBP4 are associated with severe pediatric sepsis.

Yidi Qin, Kate F Kernan, Yulong Bai, John R Shaffer, Zsolt Urban, Scott Canna, Murray M Pollack, Kathleen Meert, Christopher Newth, Tom Shanley and 4 more

Abstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Pediatric research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Yidi QinDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Kate F KernanDivision of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, Faculty Pavilion, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Yulong BaiDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
John R ShafferDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Zsolt UrbanDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Scott CannaDepartment of Pediatrics, Children's Hospital of Philadelphia, Immune Dysregulation Program, Division of Rheumatology, University of Pennsylvania School of Medicine, Pittsburgh, PA, USA.
Murray M PollackDivision of Critical Care Medicine, Department of Pediatrics, Children's National Hospital, Washington DC, USA.
Kathleen MeertDivision of Critical Care Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA.
Christopher NewthDivision of Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Tom ShanleyDivision of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, Ann Arbor, MI, USA.
Rick E HarrisonDivision of Critical Care Medicine, Department of Pediatrics, Mattel Children's Hospital at University of California Los Angeles, Los Angeles, CA, USA.
Mark HallDivision of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital Immune Surveillance Laboratory, and Nationwide Children's Hospital, Columbus, OH, USA.
Joseph A CarcilloDivision of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, Faculty Pavilion, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Hyun-Jung ParkDepartment of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. hyp15@pitt.edu.

Funding

Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure RenewalR01GM108618 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOSEPH A CARCILLO · 2014 to 2026
$5.4M
NIGMS NIH HHS R01 GM108618
6 · The paper itself

Abstract

backgroundSepsis is a leading global health burden in children, and its unavoidable heterogeneity has hindered providing therapies beyond antibiotics and supportive care. Recently, we identified four computable phenotypes showing distinct cytokine profiles, clinical outcomes, and therapeutic response characteristics (PedSep-A, B, C, and D) in a multicenter pediatric sepsis cohort.

methodsIn the cohort data, we collected whole-exome sequencing data and identified rare variants associated with PedSep-D phenotype by conducting a gene-based analysis in an aggregated fashion.

resultsAs a result, one whole-exome significant gene (LTBP4) and two suggestive significant genes (PLA2G4E, CCDC157) showed association with PedSep-D, the phenotype characterized by the most severe outcomes and highest inflammation. The associated variants in LTBP4 were enriched for predicted deleterious effects based on established functional prediction metrics. All three associated genes are implicated in inflammation and immune cell activation based on existing gene function and expression data. Although the circulating cytokine profiles were overlapping between the rare variant carriers, we also identified gene-specific cytokine changes.

conclusionAltogether, our study provides valuable insights into the genetic architecture of a pediatric sepsis phenotype with the highest inflammation level and the most severe outcomes, highlighting potential candidate genes and pathways for further biomarker and therapeutic studies. IMPACT: Pediatric sepsis exhibits substantial heterogeneity, with genetic variation contributing to this variability. Rare variants in LTBP4 are significantly associated with the most severe pediatric sepsis phenotype (PedSep-D), while variants in PLA2G4E and CCDC157 show associations with this phenotype in suggestive significance. Expands on the concept of sepsis phenotypes (PedSep-A, B, C, D) by incorporating genetic insights, moving beyond clinical and cytokine profiles to uncover molecular drivers. Opens new avenues for mechanistic studies to understand the genetic underpinnings of severe inflammation and immune activation in sepsis.

Indexed as

Genetic VariationLatent TGF-beta Binding ProteinsSepsisChildChild, PreschoolCytokinesExome SequencingFemaleGenetic Predisposition to DiseaseHumansInfantMalePhenotypeCytokinesLatent TGF-beta Binding ProteinsLTBP4 protein, human

Identifiers

PMID41076474
PMCPMC13182162

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.