The Causal Effect of Iron Traits on Risk of Hypertrophic Scarring: A Two‐Sample Mendelian Randomization Study

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BACKGROUND: The involvement of iron deficiency anemia (IDA) and abnormal iron metabolism in multiple fibrotic diseases is known, but their precise relationship with hypertrophic scarring (HTS) remains uncertain. AIM: This study aimed to explore whether there are causal associations between iron traits-such as IDA, transferrin (TF), transferrin saturation (TFS), ferritin (FERR), and IRON levels-and the risk of HTS using a two-sample Mendelian randomization (MR) approach. METHODS: Relevant consortia provided genome-wide association study (GWAS) data for iron traits, while the FinnGen study supplied GWAS data for HTS. Stringent criteria for instrumental variable (IV) selection were applied, and MR analyses were performed using the inverse-variance weighted (IVW) method as the primary analysis, along with MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including the MR-Egger intercept, Cochran's Q test, leave-one-out analysis, and MR-PRESSO, were utilized to assess horizontal pleiotropy, heterogeneity, and outlier effects. RESULTS: The MR analyses did not indicate significant causal links between IDA, TF, FERR, or IRON levels and the risk of HTS. While the IVW method proposed a potential protective effect of elevated TFS levels (OR = 0.69, 95% CI: 0.51-0.93, p = 0.0155) on HTS risk, the results varied across different MR methods. Sensitivity analyses found no significant pleiotropy or heterogeneity. CONCLUSION: The two-sample MR study did not find compelling evidence for causal associations between most iron traits and HTS risk. However, the IVW method pointed to a potential protective effect of elevated TFS levels on HTS risk. Further investigation is necessary to explore the role of iron metabolism in scarring.

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