Causal relationships of serum iron metabolites with sepsis and cardiomyopathy: a Mendelian randomization analysis

The study aims to investigate the causal relationships of serum iron (SI) metabolites with sepsis and cardiomyopathy as two distinct outcomes.

Genome-wide association studies (GWAS) data for SI, serum ferritin (SF), serum transferrin (STF), transferrin receptor (TFRC), sepsis, and cardiomyopathy were obtained from the EBI website. Transferrin saturation percentage (TSP) data were from the Genetics of Iron Status Consortium. Due to lack of GWAS for acute sepsis-induced cardiomyopathy (SIC), cardiomyopathy GWAS was used as a genetic proxy. Causal relationships were analysed using inverse-variance weighting, MR-Egger, weighted median, simple mode, and weighted mode methods. Power calculations, Cochran's Q test, MR-PRESSO, and Steiger directionality test were performed for quality control.

In the analysis of iron metabolites and cardiomyopathy, there were 2 single nucleotide polymorphisms (SNPs) in SI (mean F-statistic = 12.3), 69 SNPs in SF (mean F-statistic = 28.7), 3 SNPs in STF (mean F-statistic = 15.2), 2 SNPs in TFRC (mean F-statistic = 11.8), and 24 SNPs in TSP (mean F-statistic = 22.4); and SF was a risk factor for cardiomyopathy (OR = 1.750, 95%CI: 1.152~2.657, P = 0.009). Furthermore, in the analysis of iron metabolites and sepsis, there were 2 SNPs in SI, 86 SNPs in SF, 4 SNPs in STF, 4 SNPs in TFRC, and 29 SNPs in TSP; and SF was a risk factor of sepsis (OR = 3.079, 95%CI: 1.420~6.679, P = 0.004). The Steiger directionality test confirmed that the causal direction was from ferritin to both outcomes. The results of quality control revealed no heterogeneity or horizontal pleiotropy among SNPs. In addition, there was no significant change in the MR analysis results after the removal of single SNP.

SF may increase the risk of both sepsis and cardiomyopathy, potentially through inflammation-iron metabolism pathways rather than direct iron toxicity.