Genetic susceptibility to aseptic loosening following total hip and knee arthroplasty: a systematic review of candidate-gene and genome-wide association studies.

INTRODUCTION: Aseptic loosening is the leading cause of revision after total hip (THA) and knee (TKA) arthroplasty, accounting for 33%-50% of revisions. Variable individual susceptibility suggests genetic contributions. SOURCES OF DATA: Five databases searched to 9 June 2026. Studies reporting genetic associations with aseptic loosening or osteolysis in THA/TKA were included. Quality was assessed via Q-Genie. Pooled odds ratios (random-effects) were computed for loci with ≥3 independent studies (TNF-α -308G > A, IL-6 -174G > C). Meta-analysis for MMP-1 rs5854 was not possible because of insufficient replication. AREAS OF AGREEMENT: Twenty-six studies (7419 participants) examined THA or mixed cohorts; none studied TKA alone. Seventeen gene loci were implicated (cytokines, bone remodelling, matrix degradation, etc.). Pooled analysis: TNF-α -308G > A OR 1.94 (95% CI 1.28-2.93; I2 = 38%; 3 studies); IL-6 -174G > C OR 1.61 (95% CI 1.07-2.42; I2 = 51%; 3 studies). IL-1RN VNTR 498 bp allele conferred ~ 4-fold risk in atopic patients. Variants in RANK, KREMEN2, OPG, SFRP1, TIRAP, and BCL2 were also associated. GNAS1 and CALCA showed no association. Quality was low to moderate. No genome wide association studies (GWAS) was identified. AREAS OF CONTROVERSY: Evidence is dominated by small, single-centre, candidate-gene studies in Caucasian THA cohorts, with heterogeneity in surgery, implants, and phenotype definitions. GROWING POINTS: IL1RN-atopy interaction enables pre-surgical screening. IL-6 genotyping may personalize monitoring. Biobank-registry linkage now permits adequately powered GWAS. AREAS TIMELY FOR DEVELOPING RESEARCH: A well-powered GWAS using registry-biobank linkage; independent replication of RANK/OPG/Wnt and IL1RN findings; first TKA-specific genetic studies; standardized phenotype definitions.