Decoding the Causal Effects of Blood-Related Phenotypes in Hypertrophic Scars and Keloids: A Mendelian Randomization...

Hypertrophic scars (HS) and keloids are pathological outcomes of aberrant wound healing. Their association with systemic physiological factors remains unclear. Mendelian randomization (MR) uses genetic variants as instrumental variables (IVs) to infer causality, minimizing confounding factors.

In this study, we aim to investigate the causal effects of blood-related phenotypes, including blood cell counts, blood pressure, lipids, and glucose, on the risk of HS and keloids using a two-sample MR method.

Genetic instruments for exposures were obtained from publicly available GWAS summary statistics, while outcome data were sourced from the FinnGen database and GWAS Catalog. The IVs were selected based on genome-wide significance (P < 5 × 10^-8) and clumped for independence (r² < 0.001, window = 10,000 kb), with F-statistic > 10 and minor allele frequency > 0.01 applied to minimize weak instrument bias. Causal estimates were primarily derived using the inverse variance weighted method, supplemented by comprehensive sensitivity analyses including heterogeneity, pleiotropy, and reverse causality.

Genetically predicted higher leukocyte (OR: 1.175, 95% CI: 1.049-1.315, P = 0.005) and neutrophil counts (OR: 1.177, 95% CI: 1.040-1.332, P = 0.010) were causally associated with increased keloid risk. Conversely, lower systolic blood pressure (SBP) (OR: 0.709, 95% CI: 0.537-0.938, P = 0.016) and diastolic blood pressure (DBP) (OR: 0.732, 95% CI: 0.565-0.949, P = 0.018) were causally linked to higher HS risk, and lower SBP (OR: 0.760, 95% CI: 0.622-0.928, P = 0.007) was associated with increased keloid risk. No causal relationships were found for other blood cells, lipids, or glucose with either scar type. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy, supporting the robustness of the main findings.

Our study suggests the causal effects of blood-related phenotypes in HS and keloids by using an MR method. Our results offer novel etiological insights and a potential perspective for scar-related intervention.