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Genetic Regulation of Protein Biomarkers in Pediatric Acute Respiratory Distress Syndrome
Guy Helman1, Rui Feng2, Joshua E Motelow3
1Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA.
Insights
We found a specific gene variant (SNP) in SFTPD that affects protein biomarker levels in children with acute respiratory distress syndrome (ARDS). This genetic factor influences ARDS subphenotypes but did not impact survival rates in our study.
Area of Science:
- Genetics
- Pediatric Critical Care Medicine
- Biomarker Discovery
Background:
- Acute respiratory distress syndrome (ARDS) in children presents significant morbidity and mortality.
- Protein biomarkers are crucial for understanding pediatric ARDS heterogeneity and subphenotyping.
- Genetic factors may influence biomarker levels and contribute to ARDS subphenotypes.
Purpose of the Study:
- To investigate the genetic contribution to protein biomarker levels in pediatric ARDS.
- To identify genetic variants associated with biomarkers used for subphenotyping.
- To explore the impact of genetic associations on ARDS patient outcomes.
Main Methods:
- Retrospective cohort study of pediatric ARDS patients (<18 years).
- Genome-wide protein quantitative trait loci (pQTL) analysis on day 0 ARDS biomarkers.
- Linear mixed-effects models for longitudinal biomarker analysis.
- Cox proportional hazard models for 28-day survival analysis.
Main Results:
- A single nucleotide polymorphism (SNP) in the SFTPD gene showed a cis-regulatory effect on biomarker levels.
- The identified SNP significantly impacted biomarker levels in carriers on day 0 of ARDS.
- No significant association was found between the SNP and 28-day mortality risk.
- The study analyzed 333 children with ARDS, with 267 undergoing pQTL analysis.
Conclusions:
- A gene-associated SNP in SFTPD influences relevant biomarker levels in pediatric ARDS.
- This finding contributes to understanding the genetic determinants of pediatric ARDS subphenotypes.
- Further research is needed to fully elucidate the role of genetic factors in ARDS biomarker regulation and subphenotyping.
Objectives:
Acute respiratory distress syndrome (ARDS) is a significant contributor to ICU admissions, morbidity, and mortality. Biomarkers have increasingly been used to dissect heterogeneity and mechanisms underlying pediatric ARDS. We sought to assess the genetic contribution to the levels of protein biomarkers currently used to subphenotype pediatric ARDS patients.
Design, Setting, And Participants:
Retrospective, single-center cohort study at a tertiary care PICU of children (< 18 yr) with pediatric ARDS diagnosis.
Interventions:
None.
Measurements And Main Results:
Genome-wide protein quantitative trait loci (pQTL) analysis was performed on biomarkers measured on day 0 of ARDS, which were previously associated with outcomes from a single-center cohort using linear regression models. We then assessed the genetic association with longitudinal biomarker levels (on days 0, 3, and 7) and with 28-day survival using linear mixed-effects models and Cox proportional hazard models, respectively. From 333 children with ARDS, 267 underwent pQTL analysis against 6 preselected protein biomarkers. Among the patients, 49.4% had ARDS attributed to infectious pneumonia, and 21.7% had ARDS resulting from nonpulmonary sepsis. The hypoinflammatory phenotype was identified in 74.2% of patients, and overall mortality was 14.6%. One single nucleotide polymorphism (SNP) was identified in SFTPD with presumed cis-regulatory effect. Linear mixed-effect modeling confirmed the effect of the SNP on biomarker levels in heterozygous or homozygous carriers on day 0 of ARDS course. Survival analysis demonstrated no significant impact on mortality risk.
Conclusions:
We identified a gene-associated SNP in SFTPD that impacts relevant biomarker levels in pediatric ARDS. Further characterization is needed to better understand subphenotypes in pediatric ARDS, including genetic determinants of the biomarker levels used to define them.
