Risk factors for non-responsiveness to 5-aminosalicylic acid in patients with ulcerative colitis identified using retrospective clinical study and Mendelian randomization

This study aimed to identify risk factors and potential targets associated with non-responsiveness to 5-Aminosalicylic acid (5-ASA) in patients with ulcerative colitis (UC). Patients with mild to moderate UC were grouped based on their responsiveness to 5-ASA. Regression analysis was conducted to identify risk factors for non-responsiveness, while Mendelian randomization (MR) analysis was used to evaluate the potential targets. Among 50 patients (11 non-responders and 39 responders), non-responders exhibited higher incidences of fever, back pain, allergy history, and ankylosing spondylitis, as well as elevated monocyte count and alanine aminotransferase (ALT) level, but a lower aspartate aminotransferase-to-ALT (AST/ALT) ratio (all P < 0.05). Allergy history was a risk factor (OR 140.50, P = 0.021), while a high AST/ALT ratio was a protective factor (OR 0.001, P = 0.023) for non-responsiveness. The area under the receiver operating characteristic curve for the AST/ALT ratio was 0.80. MR analysis showed that inhibition of the inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK) by 5-ASA, targeting ALT, increased the risk of UC (OR 1.02, P = 0.002). Our findings suggested that allergy history and the AST/ALT ratio were associated with non-responsiveness to 5-ASA, and CHUK was identified as a potential target for ALT-related non-responsiveness.Trial Registration: ChiCTR2400084086|| http://www.chictr.org.cn/ , Chinese Clinical Trial Registry, 2024-05-10.