Burn and multi-omic biomarkers: causal relationships with 41 inflammatory factors and 35 blood and urine markers

Abstract

BACKGROUND: Conventional observational studies are inadequate to reveal the potential causal relationship of biomarkers in burns patients. Mendelian randomization, leveraging genetic variation as an instrumental variable to mimic the advantages of randomized controlled trials, has emerged as a crucial tool for dissecting causal associations in complex diseases. OBJECTIVE: To explore the relationship of burn injury with 41 inflammatory cytokines and 35 blood and urinary biomarkers using Mendelian Randomization. METHODS: (1) Burn-related data of genome-wide association studies were obtained from the IEU open GWAS project database, constructed by The University of Bristol, UK, including 218 131 samples and 16 380 465 single nucleotide polymorphisms were included in the study. (2) Data for 41 types of inflammatory cytokines were derived from a study involving 8 293 participants in the Finnish Young Cardiovascular Risk Study database, which is constructed by the Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku. (3) Data for 35 types of blood and urinary biomarkers were derived from a study involving 363 228 participants from the UK Biobank, which is a large biomedical database project jointly initiated by the UK government, the Wellcome Trust, and the Medical Research Council of the UK. Single nucleotide polymorphisms were employed as instrumental variables, and analyses were conducted using inverse variance weighting, MR Egger, weighted median, and weighted mode methods. Cochrane's Q test was used to identify heterogeneity, and MR Egger intercept test, MR-PRESSO test, and leave-one-out analysis were used to assess the reliability of exposure-outcome associations. RESULTS AND CONCLUSION: Burn injury reduced levels of interleukin-9 (OR=0.97; 95%CI, 0.949 to 0.997; P=0.030) and testosterone (OR=0.997; 95%CI, 0.995 to 0.999; P=0.025), with no heterogeneity or horizontal pleiotropy, demonstrating robustness. The Mendelian randomization analysis indicates that burn injury leads to decreased levels of interleukin-9 and testosterone, suggesting that increasing these levels may aid in tissue repair and improve protein breakdown rate after burn.

1. Introduction

Burn injury poses a serious threat to patients' life and health [1]. According to the World Health Organization, over 11 million people suffer burns annually worldwide, with a high mortality rate, estimated at over 250,000 deaths per year [2]. As a complex systemic trauma, the pathophysiological process of burns is characterized by excessive inflammatory response, metabolic disturbances, and multiple organ dysfunction, accompanied by systemic changes such as immunosuppression, endocrine axis (e.g., hypothalamic-pituitary-gonadal axis, HPG axis) imbalance, and oxidative stress damage [3-4]. These pathological changes not only directly cause tissue damage but may also exacerbate complications, including infection, multiple organ failure, and chronic non-healing wounds, through dysregulation of inflammatory cytokine networks and metabolic reprogramming (e.g., accelerated protein breakdown and increased energy expenditure under hypermetabolic states) [5]. Even after discharge, burn survivors continue to struggle with physical and psychological issues, such as skin problems, anxiety, depression, and post-traumatic stress disorder [6].

However, traditional observational studies are difficult to clarify the causal relationship between burns and biomarkers, as they are susceptible to confounding factors (e.g., age, underlying diseases) and reverse causation bias (e.g., biomarker changes may be a consequence rather than a cause of burns).