Abstract
Alopecia areata (AA) is an autoimmune hair loss disorder that affects approximately 2% of the global population, imposing a substantial psychological burden and impairing the quality of life. Although observational studies have correlated blood metabolites with AA, these associations are susceptible to confounding and reverse causality, leaving the causal direction unclear. This study employed a 2-sample Mendelian randomization (MR) approach to infer the causal relationship between blood metabolites and AA. This study used publicly available genome-wide association study summary statistics for blood metabolites (Kettunen et al, N = 24,925) and AA (FinnGen, 682 cases/361,140 controls), both based on European ancestry populations. Single-nucleotide polymorphisms significantly associated with metabolites were selected as instrumental variables, while those in linkage disequilibrium or with an F-statistic < 10 were excluded to ensure the robustness of the instruments. The primary analysis utilized the inverse variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO analyses to assess horizontal pleiotropy and heterogeneity. A leave-one-out sensitivity analysis was performed to evaluate the influence of individual single-nucleotide polymorphisms. Forward MR analysis identified 25 blood metabolites suggesting potential causal effects on AA. Specifically, glutamine exhibited a protective effect (odds ratio [OR] = 0.59, 95% confidence interval [CI]: 0.35-0.99). Positive associations were observed for the ratio of free cholesterol to cholesterol esters (OR = 1.34, 95% CI: 1.04-1.74), serum total cholesterol (OR = 1.31, 95% CI: 1.02-1.68), citric acid (OR = 2.89, 95% CI: 1.41-5.92), and glucose (OR = 1.99, 95% CI: 1.01-3.92). Notably, lipoprotein-related metabolites accounted for the majority of significant findings (80%; 20/25). Reverse MR analysis did not support reverse causality. Sensitivity analyses confirmed the robustness of these associations, with no significant horizontal pleiotropy or heterogeneity detected. Our study suggests potential causal associations between blood levels of glutamine, citric acid, glucose, various lipids, and lipoproteins with AA. Initial analyses found no evidence of reverse causality. These findings require further investigation for validation.