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

Li Gao; Nicholas Rafaels; Tanda M Dudenkov; Mahendra Damarla; Rachel Damico; James P Maloney; Marc Moss; Greg S Martin; Jonathan Sevransky; Carl Shanholtz; Dan L Herr; Joe G N Garcia; Tamara Hernandez-Beeftink; Jesús Villar; Carlos Flores; Terri H Beaty; Roy Brower; Paul M Hassoun; Kathleen C Barnes

doi:10.1186/s12931-023-02481-8

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

Respir Res. 2023 Jul 6;24(1):177. doi: 10.1186/s12931-023-02481-8.

Authors

Li Gao^{1

2}, Nicholas Rafaels³, Tanda M Dudenkov⁴, Mahendra Damarla⁵, Rachel Damico⁵, James P Maloney⁶, Marc Moss⁶, Greg S Martin⁷, Jonathan Sevransky⁷, Carl Shanholtz⁸, Dan L Herr⁸, Joe G N Garcia⁹, Tamara Hernandez-Beeftink^{10

11}, Jesús Villar^{11

12

13}, Carlos Flores^{10

12

14

15}, Terri H Beaty⁴, Roy Brower⁵, Paul M Hassoun^{16

17}, Kathleen C Barnes^{18

19}

Affiliations

¹ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. lgao2@jhmi.edu.
² The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.65B, Baltimore, MD, 21224, USA. lgao2@jhmi.edu.
³ Division of Biomedical Informatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁴ Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁸ University of Maryland School of Medicine, Baltimore, MD, USA.
⁹ University of Arizona College of Medicine, Tucson, AZ, USA.
¹⁰ Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
¹¹ Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
¹² CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
¹³ Li Ka Shing Knowledge Institiute at St. Michael's Hospital, Toronto, Canada.
¹⁴ Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain.
¹⁵ Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
¹⁶ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. phassou1@jhmi.edu.
¹⁷ The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.65B, Baltimore, MD, 21224, USA. phassou1@jhmi.edu.
¹⁸ Division of Biomedical Informatics & Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA. Kathleen.Barnes@cuanschutz.edu.
¹⁹ University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, Room 5330A, Aurora, CO, 80045, USA. Kathleen.Barnes@cuanschutz.edu.

Abstract

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: 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: 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_adjusted<0.0005 and 0.0006, respectively), suggesting a role in increased risk of renal dysfunction. In contrast, among EA ARDS patients, the missense variant rs17011368 (I703V) was associated with enhanced mortality at 60-days (P < 0.038). We found higher serum XOR activity in 143 sepsis patients (54.5 ± 57.1 mU/mL) compared to 31 controls (20.9 ± 12.4 mU/mL, P = 1.96 × 10^{- 13}). XOR activity was associated with the lead variant rs185925 among AA sepsis patients with ARDS (P < 0.005 and P_adjusted<0.01). Multifaceted functions of prioritized XDH variants, as suggested by various functional annotation tools, support their potential causality in sepsis.

Conclusions: Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Keywords: Acute respiratory distress syndrome; Biomarker; Haplotype; Sepsis; Single nucleotide polymorphism; Xanthine oxidoreductase.

MeSH terms

Genotype
Humans
Polymorphism, Single Nucleotide / genetics
Respiratory Distress Syndrome*
Sepsis* / complications
Sepsis* / diagnosis
Sepsis* / genetics
Xanthine Dehydrogenase / genetics

Substances

Xanthine Dehydrogenase

Grants and funding

P50 HL073994/HL/NHLBI NIH HHS/United States