Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure.

Humans Xanthine Dehydrogenase / genetics Genotype Respiratory Distress Syndrome Polymorphism, Single Nucleotide / genetics Sepsis / diagnosis
Acute respiratory distress syndrome Biomarker Haplotype Sepsis Single nucleotide polymorphism Xanthine oxidoreductase

Journal

Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633

Informations de publication

Date de publication:
06 Jul 2023
Historique:
received: 14 04 2023
accepted: 20 06 2023
medline: 10 7 2023
pubmed: 7 7 2023
entrez: 6 7 2023
Statut: epublish

Résumé

Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis. We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets. Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (P Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Sections du résumé

BACKGROUND BACKGROUND
Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis.
METHODS METHODS
We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets.
RESULTS RESULTS
Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (P
CONCLUSIONS CONCLUSIONS
Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Identifiants

DOI: 10.1186/s12931-023-02481-8 PMID: 37415141 PMC: PMC10324226
pubmed: 37415141
doi: 10.1186/s12931-023-02481-8
pii: 10.1186/s12931-023-02481-8
pmc: PMC10324226
doi:

Substances chimiques

Xanthine Dehydrogenase EC 1.17.1.4

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

177

Subventions

Organisme : NHLBI NIH HHS
ID : P50 HL073994
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Li Gao (L)

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. lgao2@jhmi.edu.
The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.65B, Baltimore, MD, 21224, USA. lgao2@jhmi.edu.

Nicholas Rafaels (N)

Division of Biomedical Informatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

Tanda M Dudenkov (TM)

Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.

Mahendra Damarla (M)

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Rachel Damico (R)

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

James P Maloney (JP)

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

Marc Moss (M)

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

Greg S Martin (GS)

Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Jonathan Sevransky (J)

Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Carl Shanholtz (C)

University of Maryland School of Medicine, Baltimore, MD, USA.

Dan L Herr (DL)

University of Maryland School of Medicine, Baltimore, MD, USA.

Joe G N Garcia (JGN)

University of Arizona College of Medicine, Tucson, AZ, USA.

Tamara Hernandez-Beeftink (T)

Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.

Jesús Villar (J)

Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
Li Ka Shing Knowledge Institiute at St. Michael's Hospital, Toronto, Canada.

Carlos Flores (C)

Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain.
Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.

Terri H Beaty (TH)

Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.

Roy Brower (R)

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Paul M Hassoun (PM)

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. phassou1@jhmi.edu.
The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.65B, Baltimore, MD, 21224, USA. phassou1@jhmi.edu.

Kathleen C Barnes (KC)

Division of Biomedical Informatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA. Kathleen.Barnes@cuanschutz.edu.
University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, Room 5330A, Aurora, CO, 80045, USA. Kathleen.Barnes@cuanschutz.edu.

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