Reassessing host genetic susceptibility to tick-borne encephalitis: evidence from a systematic review and meta-analysis.

Abstract

Background: Host genetic factors have been proposed to influence susceptibility to tick-borne encephalitis (TBE), but findings from candidate-gene association studies have been inconsistent.

Objective: To evaluate evidence for common genetic variants associated with TBE susceptibility and severity by synthesising candidate-gene and genome-wide association study (GWAS) data.

Methods: Data source: PubMed and Web of Science were searched for studies published between January 2005 and December 2025 following PRISMA 2020 guidelines.

Study eligibility criteria: Case-control studies of laboratory-confirmed TBE reporting genotype or allele frequencies sufficient to estimate effect sizes.

Participants: The review included 16 candidate-gene studies and one European consortium GWAS, comprising 3,759 patients with TBE (1,521 mild; 1,454 severe) and 11,771 controls from nine countries. Assessment of risk of bias: Methodological quality was assessed using the Q-Genie tool.

Methods: of data synthesis: Random-effects meta-analyses were performed for variants investigated in ≥4 datasets. Heterogeneity, publication bias, subgroup analyses, and minimum detectable odds ratios (MDORs) were assessed.

Results: Four variants met the criteria for quantitative synthesis. No significant associations with TBE susceptibility were observed for CCR5 rs333 (OR = 1.12, 95% CI = 0.98-1.29), TLR3 rs3775291 (OR = 0.87, 95% CI = 0.68-1.10), IL10 rs1800872 (OR = 0.97, 95% CI = 0.88-1.08), or CD209 rs2287886 (OR = 0.96, 95% CI = 0.80-1.15). Analyses of severe disease yielded similarly null results. MDOR analyses indicated adequate power to detect moderate genetic effects (OR≈1.12-1.18), indicating that any true effects are likely to be small.

Conclusions: This study provides the most comprehensive synthesis of TBE genetic association studies to date and demonstrates that the most extensively investigated genetic variants are unlikely to serve as clinically useful predictors of TBE susceptibility or severity, supporting genome-wide discovery, rare variant analyses, and integrative approaches to identify biologically relevant host determinants of TBE.