1. School of Nursing, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China; 2. Tongji University, Shanghai 200092, China; 3. Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, China
Abstract：Objective To evaluate the association between Crohn's disease (CD) and frailty using a Mendelian randomization (MR) approach, so as to provide the evidence for prevention and control strategies. Methods Genetic association data for CD were collected through the International Inflammatory Bowel Disease Genetics Consortium, with 20 883 samples and 12 276 506 single nucleotide polymorphism (SNP), and genetic association data for frailty were collected through a meta-analysis including 175 226 samples and 7 589 717 SNPs. A forward MR analysis was performed using the inverse-variance weighted (IVW) method with 37 CD-associated SNPs as instrumental variables, and frailty as the study outcome, and a reverse MR analysis was performed with 13 frailty-associated SNPs as instrumental variables and CD as the study outcome. The heterogeneity was assessed using the Cochran's Q test, and the horizontal pleiotropy was assessed using the MR-PRESSO global test and MR-Egger regression. In addition, the robustness of the results was verified with the leave-one-out. Results Forward MR analysis results showed that patients with genetically predicted CD had an increased risk of frailty index relative to those without CD (β=0.018, 95%CI: 0.011-0.026, P<0.05). Cochran's Q test detected no heterogeneity (P>0.05), and neither the MR-PRESSO test nor the MR-Egger regression revealed horizontal pleiotropy of instrumental variables (both P>0.05). Leave-one-out analysis showed robustness of the MR analysis results. Reverse MR analysis showed no association between frailty index and the risk of CD (OR=0.740, 95%CI: 0.206-2.661, P>0.05). Conclusions Genetically predicted CD is associated with an increased risk of frailty. It is suggested that screening and prevention of frailty should be reinforced among CD patients.
[1] HOOGENDIJK E O,AFILALO J,ENSRUD K E,et al.Frailty:implications for clinical practice and public health[J]. Lancet,2019,394(10206):1365-1375. [2] 中华医学会消化病学分会炎症性肠病学组. 炎症性肠病诊断与治疗的共识意见(2018年,北京)[J]. 中华消化杂志,2018,38(5):292-311. [3] QIAN A S,NGUYEN N H,ELIA J,et al.Frailty is independently associated with mortality and readmission in hospitalized patients with inflammatory bowel diseases[J]. Clin Gastroenterol Hepatol,2021,19(10):2054-2063. [4] YOU L,BAI C,WANG S,et al.The prevalence and factors that impact frailty in inflammatory bowel disease patients hospitalized in a tertiary hospital in China[J]. Dig Dis,2023,41(3):396-404. [5] WOLF J H,HASSAB T,D'ADAMO C R,et al. Frailty is a stronger predictor than age for postoperative morbidity in Crohn's disease[J]. Surgery,2021,170(4):1061-1065. [6] SINGH S,BOLAND B S,JESS T,et al.Management of inflammatory bowel diseases in older adults[J]. Lancet Gastroenterol Hepatol,2023,8(4):368-382. [7] EMDIN C A,KHERA A V,KATHIRESAN S.Mendelian randomization[J]. JAMA,2017,318(19):1925-1926. [8] LIU J Z,VAN S S,HUANG H,et al.Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations[J]. Nat Genet,2015,47(9):979-986. [9] ATKINS J L,JYLHAVA J,PEDERSEN N L,et al. A genome-wide association study of the frailty index highlights brain pathways in ageing[J/OL]. Aging Cell,2021,20(9)[2023-10-23]. https://doi.org/10.1111/acel.13459. [10] BURGESS S,BUTTERWORTH A,THOMPSON S G.Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol,2013,37(7):658-665. [11] BURGESS S,THOMPSON S G.Interpreting findings from mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol,2017,32(5):377-389. [12] YANG S,PUDASAINI R,ZHI H,et al.The relationship between blood lipids and risk of atrial fibrillation:univariable and multivariable Mendelian randomization analysis[J]. Nutrients,2021,14(1):1-10. [13] SINGH S,BOLAND B S,JESS T,et al.Management of inflammatory bowel diseases in older adults[J]. Lancet Gastroenterol Hepatol,2023,8(4):368-382. [14] TAYLOR J A,GREENHAFF P L,BARTLETT D B,et al.Multisystem physiological perspective of human frailty and its modulation by physical activity[J]. Physiol Rev,2023,103(2):1137-1191. [15] 侯晓婷,孟欢,薛佳辰,等.关于炎症性肠病发病机制的研究进展[J]. 中国比较医学杂志,2023,33(9):138-148. [16] HOPKIN S,LORD J M,CHIMEN M.Dysregulation of leukocyte trafficking in ageing:causal factors and possible corrective therapies[J/OL]. Pharmacol Res,2021,163[2023-10-23]. https://doi.org/10.1016/j.phrs.2020.105323. [17] 王凌,尤鸿美,潘雪银,等.老年性疾病通过cGAS-STING通路调控衰老相关分泌表型[J]. 中国药理学通报,2021,37(4):450-454. [18] WANG X,BOOTSMA H,KROESE F,et al. Senescent stem and transient amplifying cells in Crohn's disease intestine[J/OL]. Inflamm Bowel Dis,2020,26(2)[2023-10-23]. https://doi.org/10.1093/ibd/izz295.
