Investigating Potential Causal Relationships Between Plasma Protein Ratios and Alopecia Areata: A Bidirectional Mendelian Randomization Study

Aims/Background Several types of plasma protein ratios (PPRs) have been shown to have significant associations with alopecia areata (AA); however, their causal relationships remain to be elucidated. This study aimed to identify causal relationships of 2821 PPRs with AA. Methods Data from the United Kingdom Biobank Pharma Proteomics Project (n > 54,000) and FinnGen R11 data (862 cases/432,686 controls) were used for a bidirectional Mendelian randomization (MR) analysis. Inverse-variance weighting (IVW), weighted median, simple mode, weighted mode and MR-Egger regression tests were used to estimate the causality between PPRs and AA. Sensitivity analyses were performed to ensure the robustness of our findings. Results Our analysis showed that the agrin (AGRN)/heparan sulfate proteoglycan 2 (HSPG2) and 2,4-dienoyl-CoA reductase 1 (DECR1)/FK506-binding protein 1B (FKBP1B) ratios were significantly elevated in AA patients (p < 0.05). The IVW method revealed that for every one standard deviation (SD) increase in the AGRN/HSPG2 ratio, the risk of AA increased by 44.8% (odds ratio [OR] = 1.448, 95% confidence interval [CI]: 1.200–1.745, p < 0.001). Similarly, for every one SD increase in the DECR1/FKBP1B ratio, the risk of AA increased by 65.8% (OR = 1.658, 95% CI: 1.273–2.159, p < 0.001). In contrast, reverse MR analysis did not detect any significant causal effects of AA on these two PPRs (p > 0.05). Sensitivity analyses confirmed the robustness of our results and ruled out horizontal pleiotropy (MR-Egger intercept p > 0.05). Conclusion This study uncovered the causal relationships between two types of PPRs and AA, offering new insights into the diagnosis, treatment, and underlying mechanisms of AA.