S1001 Fatigue Status and Risk of Inflammatory Bowel Disease: A Longitudinal Cohort Study and Mendelian Randomization Analysis

Introduction: Fatigue has garnered significant attention due to its detrimental effects on overall health and well-being. Fatigue was previously considered as a common symptom of Inflammatory Bowel Disease (IBD). However, approximately 50% of patients with IBD have experienced fatigue before their initial diagnosis. Whether fatigue is the cause or result of IBD remains unknown. Thus, this study was to explore the causal association between fatigue and IBD. Methods: Our observational analysis was based on UK Biobank, a population-based cohort. 478 262 participants aged 37 - 73 were enrolled from 2006 to 2010 with complete information on the frequency of tiredness questionnaire at baseline. We classified the participants into 2 or 4 groups based on the frequency of tiredness. We used Cox proportional hazards models to examine the hazard ratio (HR) and 95% confidence interval (CI) for incident IBD, CD (Crohn's disease) or UC (ulcerative colitis) after adjusting for potential confounders. Participants were categorized into different genetic risk groups, including high, intermediate, and low groups, based on the polygenic risk score (PRS) for IBD, UC and CD for subgroup analysis. Furthermore, Mendelian randomization (MR) study was used to investigate the causality. Results: Among 478 262 participants, 61 007 (12.8%) reported fatigued status at baseline. Compared with unfatigued group, the HRs of multivariable-adjusted models for fatigued groups were 1.28 (95%CI 1.16 to 1.41) for IBD, 1.15 (1.02 to 1.30) for UC and 1.55 (1.32 to 1.56) for CD. The risks of developing IBD, UC, and CD exhibited a stepwise increase with the frequency of tiredness. The results from subgroup analysis, including in high-polygenic risk score groups, were largely consistent. MR showed the significant evidence of casual association between the frequency of tiredness with higher risk of IBD (odds ratio [OR] = 2.15, 95% CI 1.36 to 3.38, P = 0.001), UC (OR 1.88, 95% CI 1.14 to 3.12, P = 0.014) and CD (OR 2.86, 95% CI 1.64 to 4.98, P < 0.001) (Table 1). Conclusion: Our findings suggest the causality between fatigue status and IBD. Participants frequently experienced fatigue are at a higher risk of developing IBD, with a stepwise increase of risk with the frequency of tiredness. A similar association was also observed between fatigue status and risk of CD but not UC. Moreover, such associations persisted in individuals with a higher genetic risk of IBD, CD and UC. Table 1. - Associations of fatigue with the risk of IBD HR (95% CI) HR (95% CI) HR (95% CI) Non-adjusted model P Partially adjusted model P Fully adjusted model P IBD Fatigue status Not fatigued 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Fatigued 1.49 (1.36,1.63) < 0.001 1.40 (1.28,1.54) < 0.001 1.28 (1.16,1.41) < 0.001 Frequency of tiredness Not at all 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Several days 1.17 (1.09,1.27) < 0.001 1.19 (1.10,1.28) < 0.001 1.14 (1.05,1.23) 0.001 More than half the days 1.40 (1.22,1.61) < 0.001 1.37 (1.19,1.57) < 0.001 1.26 (1.09,1.45) 0.002 Nearly every day 1.81 (1.60,2.04) < 0.001 1.70 (1.49,1.93) < 0.001 1.50 (1.31,1.71) < 0.001 UC Fatigue status Not fatigued 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Fatigued 1.28 (1.14,1.43) < 0.001 1.23 (1.09,1.39) < 0.001 1.15 (1.02,1.30) 0.025 Frequency of tiredness Not at all 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Several days 1.10 (1.00,1.21) 0.040 1.13 (1.03,1.24) 0.009 1.11 (1.01,1.22) 0.033 More than half the days 1.19 (1.00,1.21) 0.051 1.18 (0.99,1.41) 0.060 1.12 (0.94,1.34) 0.206 Nearly every day 1.48 (1.27,1.73) < 0.001 1.44 (1.23,1.69) < 0.001 1.32 (1.12,1.56) 0.001 CD Fatigue status Not fatigued 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Fatigued 1.98 (1.71,2.30) < 0.001 1.80 (1.53,2.09) < 0.001 1.55 (1.32,1.82) < 0.001 Frequency of tiredness Not at all 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) Several days 1.36 (1.18,1.57) < 0.001 1.33 (1.15,1.54) < 0.001 1.23 (1.07,1.43) 0.005 More than half the days 1.99 (1.59,2.50) < 0.001 1.86 (1.47,2.34) < 0.001 1.63 (1.29,2.06) < 0.001 Nearly every day 2.64 (2.16,3.24) < 0.001 2.34 (1.86,2,84) < 0.001 1.88 (1.51,2.35) < 0.001 IBD: Inflammatory Bowel Disease; UC: Ulcerative Colitis; CD: Crohn's disease; HR: hazard ratio; CI: confidence interval.