Genome-wide association study analysis of single nucleotide variants in <i>L. infantum</i> associated with IL-6 inflammatory response in visceral leishmaniasis

Elevated levels of IL-6 in plasma are associated with the severity of visceral leishmaniasis (VL). The clinical manifestations of VL vary among patients, influenced by host factors and the virulence of the <i>Leishmania infantum</i> parasite. Considering that severe VL may result from an exaggerated inflammatory response, this study investigated whether IL-6 could serve as a biomarker to identify pro-inflammatory virulence factors. We conducted a genome-wide association study (GWAS) analysis on <i>L. infantum</i> isolates from patients with VL, whose IL-6 concentrations were measured. The analysis revealed that the relationship between IL-6 levels and clinical outcomes (survival <i>vs</i> mortality) had an area under the curve (AUC) of 0.67 (95% CI 0.52-0.81). A cut-off of 391.7 pg mL^-1 for IL-6 was established to conduct a logistic regression analysis. We identified 10 029 single nucleotide variants (SNVs) across 62 genomes, resulting in 6,948 SNVs after filtering, of which 6,341 are located in protein-coding regions. The association analysis with PLINK identified 722 variants, of which 35 showed significant associations, with odds ratios ≥3.3, primarily in coding regions. These findings demonstrate that IL-6 levels tended to be associated with the fatal outcome of VL and highlight 35 novel genetic variants that could serve as potential biomarkers for prognosis. Further research into the biological role of these variants may lead to new therapeutic targets and improve the clinical management of VL, especially in identifying high-risk patients.