Genetically Proxied Biological Aging and Risk of Hypertrophic Scar/Keloid-Coded Phenotypes: An Exploratory Two-Sample Mendelian Randomization Study

PURPOSE: Hypertrophic scars (HS), common fibroproliferative disorders, predominantly affect younger individuals. To investigate potential causal associations between multiple genetically proxied biological aging indicators and the risk of HS using a two-sample Mendelian randomization (MR) approach. PATIENTS AND METHODS: We used genome-wide association studies (GWAS) data to examine causal links between biological aging indicators (epigenetic clocks, telomere length, macroscopic aging) and HS. Primary analysis employed inverse-variance weighted MR, with sensitivity analyses (MR-Egger, weighted median, weighted mode) and multivariable MR adjusting for fibrogenic mediators. Results were validated in independent cohorts. Robustness was assessed via MR-PRESSO, Cochran's Q, MR-Steiger, and leave-one-out analyses to detect statistical evidence of directional and horizontal pleiotropy. RESULTS: Genetically predicted higher IEAA (Odds Ratio [OR]=0.926, 95% Confidence Interval [CI]: 0.878-0.976, P=0.004) and higher PhenoAge (OR=0.911, 95% CI: 0.848-0.979, P=0.011) were nominally associated with a decreased risk of HS. The PhenoAge association was consistently replicated in the independent validation cohort (OR=0.91, P=0.0059). However, these associations did not remain significant after False Discovery Rate correction. Negative control analysis showed no association with general skin fibrosis, suggesting specificity for hyper-proliferative scarring. Multivariable MR indicated that the protective effect of PhenoAge was independent of classical fibrogenic pathways. No significant causal associations were found for other aging indicators. No statistical evidence of directional or horizontal pleiotropy was detected in sensitivity analyses. CONCLUSION: This MR study provides exploratory evidence suggesting that genetically proxied faster epigenetic aging may be nominally associated with a reduced risk of HS. These findings offer novel hypotheses regarding the complex interplay between aging processes and scar formation.