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

<b>Aims/Background</b> 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. <b>Methods</b> 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. <b>Results</b> 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 (<i>p</i> < 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, <i>p</i> < 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, <i>p</i> < 0.001). In contrast, reverse MR analysis did not detect any significant causal effects of AA on these two PPRs (<i>p</i> > 0.05). Sensitivity analyses confirmed the robustness of our results and ruled out horizontal pleiotropy (MR-Egger intercept <i>p</i> > 0.05). <b>Conclusion</b> 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.