Causal relationship between folate and thrombotic external hemorrhoids: A two-sample Mendelian Randomization analysis

Thrombotic external hemorrhoids (TEH) may be influenced by micronutrient levels. This study investigates the causal relationship between TEH and 15 micronutrients, including folate, calcium, and vitamins A, C, D, E, B6, and B12. A two-sample Mendelian randomization (MR) analysis was conducted using single nucleotide polymorphisms (SNPs) associated with micronutrient levels (p < 5×10 -6 ) from genome-wide association studies (GWAS) in European populations (n=64,979 for folate). TEH outcome data were sourced from the FinnGen Biobank (n=9,749). The inverse variance weighted (IVW) method was used, with SNPs selected to ensure strong instrumental variables (F > 10). Sensitivity and pleiotropy analyses were performed. IVW analysis revealed a causal association between folate and TEH (p-value = 0.004, OR = 1.555 [95% CI 1.156–2.092] per standard deviation increase in folate levels). Sensitivity analyses confirmed the robustness of this finding. Folate is a risk factor for TEH, potentially via inflammatory pathways, providing evidence to guide clinical research and TEH management strategies. • First MR Study on Folate and TEH • This is the first Mendelian randomization (MR) study to establish a causal relationship between elevated folate levels and an increased risk of thrombotic external hemorrhoids (TEH). • Folate as a Risk Factor for TEH • Folate exhibits a significant positive causal association with TEH (IVW: P = 0.004, OR = 1.555 [1.156–2.092] ), suggesting that high folate levels may contribute to TEH development. • Mechanistic Insights • Excessive folate may promote TEH by exacerbating inflammation, disrupting vitamin B12 metabolism, and increasing thrombosis risk through vascular smooth muscle proliferation. • Robust Sensitivity Analyses • Sensitivity analyses (MR-Egger, weighted median, leave-one-out) confirm the robustness of the findings, with no evidence of pleiotropy or heterogeneity ( P > 0.05 ). • Clinical Implications • The study highlights the need for cautious folate supplementation in at-risk populations and suggests potential dietary modifications for TEH prevention. • Multivariable MR Validation • Multivariable MR analysis confirms folate’s independent effect on TEH ( P = 0.020, OR = 1.881 [1.103–2.309] ), ruling out confounding by other micronutrients like calcium and copper. • Limitations and Future Directions • Findings are based on European populations; further studies in diverse cohorts are needed. Dietary and lifestyle factors were not assessed, warranting additional research.