Causal effect between metabolic syndrome and inflammatory bowel disease: a two-sample bidirectional Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

XU Yaxin ¹ , GAO Yanan ² , XU Jun ¹ , YAO Ting ² ,  CHEN Yamei ³

1. Tongji University School of Medicine, Shanghai 200092, P. R. China;
2. School of Nursing, Anhui University of Traditional Chinese Medicine, Hefei 230038, P. R. China;
3. Department of Nursing, Tenth People's Hospital, Tongji University, Shanghai 200072, P. R. China;

Corresponding author：

CHEN Yamei, Email: Yake2023@163.com

Keywords：

Mendelian randomization; Metabolic syndrome; Inflammatory bowel disease; Causality

DOI：

10.7507/1672-2531.202310192

Video：

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Objective To investigate the bidirectional causal relationship between metabolic syndrome (MS) and inflammatory bowel disease (IBD) using Mendelian randomization (MR). Methods We extracted genetic variants with strong correlations from genome-wide association study data on MS as instrumental variables. Inverse variance weighting, MR-Egger regression methods, and weighted median methods were used to estimate the causal effect of MS and risk of developing IBD. Results Inverse variance weighting found that genetically predicted MS was associated with an increased risk of developing IBD overall (OR=1.113, 95%CI 1.020 to 1.216, P=0.017) and Crohn's disease (OR=1.195, 95%CI 1.072 to 1.333, P=0.001). And inverse MR analysis found ulcerative colitis was associated with a reduced risk of developing MS (OR=0.969, 95%CI 0.948 to 0.991, P=0.005). Conclusion The results based on MR analysis suggest that genetically predicted MS is associated with the risk of IBD as a whole and Crohn's disease and ulcerative colitis are associated with a reduced risk of developing MS.

Citation： XU Yaxin, GAO Yanan, XU Jun, YAO Ting, CHEN Yamei. Causal effect between metabolic syndrome and inflammatory bowel disease: a two-sample bidirectional Mendelian randomization study. Chinese Journal of Evidence-Based Medicine, 2024, 24(11): 1263-1269. doi: 10.7507/1672-2531.202310192 Copy

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2.	Burisch J, Jess T, Martinato M, et al. The burden of inflammatory bowel disease in Europe. J Crohns Colitis, 2013, 7(4): 322-337.
3.	Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet, 2017, 390(10114): 2769-2778.
4.	Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 56-66.
5.	Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol, 2020, 20(7): 411-426.
6.	Crooks B, Misra R, Arebi N, et al. The dietary practices and beliefs of British South Asian people living with inflammatory bowel disease: a multicenter study from the United Kingdom. Intest Res, 2022, 20(1): 53-63.
7.	Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev, 2008, 29(7): 777-822.
8.	Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet, 2005, 365(9468): 1415-1428.
9.	Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol, 2016, 31(5): 936-944.
10.	Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology, 2018, 67(1): 328-357.
11.	Argollo M, Gilardi D, Peyrin-Biroulet C, et al. Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol Hepatol, 2019, 4(8): 643-654.
12.	Dragasevic S, Stankovic B, Kotur N, et al. Metabolic syndrome in inflammatory bowel disease: association with genetic markers of obesity and inflammation. Metab Syndr Relat Disord, 2020, 18(1): 31-38.
13.	Michalak A, Mosińska P, Fichna J. Common links between metabolic syndrome and inflammatory bowel disease: current overview and future perspectives. Pharmacol Rep, 2016, 68(4): 837-846.
14.	Nagahori M, Hyun SB, Totsuka T, et al. Prevalence of metabolic syndrome is comparable between inflammatory bowel disease patients and the general population. J Gastroenterol, 2010, 45(10): 1008-1013.
15.	Hyun CK. Molecular and pathophysiological links between metabolic disorders and inflammatory bowel diseases. Int J Mol Sci, 2021, 22(17): 9139.
16.	Chen J, Xu F, Ruan X, et al. Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses. EBioMedicine, 2023, 89: 104494.
17.	Freuer D, Linseisen J, Meisinger C. Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study. BMC Med, 2022, 20(1): 82.
18.	Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease. Int J Epidemiol, 2003, 32(1): 1-22.
19.	Lind L. Genome-wide association study of the metabolic syndrome in UK biobank. Metab Syndr Relat Disord, 2019, 17(10): 505-511.
20.	de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet, 2017, 49(2): 256-261.
21.	Lai SW, Kuo YH, Liao KF. Association between inflammatory bowel disease and diabetes mellitus. Clin Gastroenterol Hepatol, 2020, 18(4): 1002-1003.
22.	Cainzos-Achirica M, Glassner K, Zawahir HS, et al. Inflammatory bowel disease and atherosclerotic cardiovascular disease: JACC review topic of the week. J Am Coll Cardiol, 2020, 76(24): 2895-2905.
23.	Chen B, Collen LV, Mowat C, et al. Inflammatory bowel disease and cardiovascular diseases. Am J Med, 2022, 135(12): 1453-1460.
24.	Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology, 2022, 75(4): 785-796.
25.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
26.	韩昕宇, 吴天强, 冯晓玲. 孟德尔随机化研究甲状腺功能减退症与多囊卵巢综合征的因果关系. 现代预防医学, 2023, 50(16): 2881-2884,2897.
27.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
28.	于天琦, 徐文涛, 苏雅娜, 等. 孟德尔随机化研究基本原理、方法和局限性. 中国循证医学杂志, 2021, 21(10): 1227-1234.
29.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
30.	Yang S, Pudasaini R, Zhi H, et al. The relationship between blood lipids and risk of atrial fibrillation: univariable and multivariable Mendelian randomization analysis. Nutrients, 2021, 14(1): 181.
31.	Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol, 2020, 17(4): 223-237.
32.	Jiang L, Li JC, Shen L, et al. Association between inflammatory bowel disease and Alzheimer's disease: multivariable and bidirectional Mendelian randomisation analyses. Gut, 2023, 72(9): 1797-1799.
33.	Oza C, Karguppikar M, Khadilkar V, et al. A pilot study to determine association of parental metabolic syndrome with development of metabolic risk in Indian children, adolescents and youth with type-1 diabetes. Diabetes Metab Syndr, 2022, 16(4): 102453.
34.	Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest, 2019, 129(10): 4001-4008.
35.	Frank DM, Bradshaw PT, Mujahid M, et al. Adolescent BMI trajectory and associations with adult metabolic syndrome and offspring obesity. Obesity (Silver Spring), 2023, 31(7): 1924-1932.
36.	Li Y, Gui J, Liu H, et al. Predicting metabolic syndrome by obesity- and lipid-related indices in mid-aged and elderly Chinese: a population-based cross-sectional study. Front Endocrinol (Lausanne), 2023, 14: 1201132.
37.	Tsaban G. Metabolic syndrome, LDL-hypercholesterolaemia, and cerebrocardiovascular risk: sex matters. Eur J Prev Cardiol, 2022, 28(18): 2018-2020.
38.	Soleimani M, Barone S, Luo H, et al. Pathogenesis of hypertension in metabolic syndrome: the role of fructose and salt. Int J Mol Sci, 2023, 24(5): 4294.
39.	Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol, 2010, 56(14): 1113-1132.
40.	Je Y, Han K, Chun J, et al. Association of waist circumference with the risk of inflammatory bowel disease: a nationwide cohort study of 10 million individuals in Korea. J Crohns Colitis, 2023, 17(5): 681-692.
41.	Chan SSM, Chen Y, Casey K, et al. Obesity is associated with increased risk of crohn's disease, but not ulcerative colitis: a pooled analysis of five prospective cohort studies. Clin Gastroenterol Hepatol, 2022, 20(5): 1048-1058.
42.	Leal Vde O, Mafra D. Adipokines in obesity. Clin Chim Acta, 2013, 419: 87-94.
43.	Korek E, Krauss H. Novel adipokines: their potential role in the pathogenesis of obesity and metabolic disorders. Postepy Hig Med Dosw (Online), 2015, 69: 799-810.
44.	Waluga M, Hartleb M, Boryczka G, et al. Serum adipokines in inflammatory bowel disease. World J Gastroenterol, 2014, 20(22): 6912-6917.
45.	Verdugo-Meza A, Ye J, Dadlani H, et al. Connecting the dots between inflammatory bowel disease and metabolic syndrome: a focus on gut-derived metabolites. Nutrients, 2020, 12(5): 1434.
46.	Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol, 2012, 13(9): R79.
47.	Jie Z, Xia H, Zhong SL, et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat Commun, 2017, 8(1): 845.
48.	任士萌, 梅璐, 黄煌, 等. 非酒精性脂肪性肝病患者肠道菌群及生物化学指标相关性分析. 中华肝脏病杂志, 2019, 27(5): 369-375.
49.	Dheer R, Davies JM, Quintero MA, et al. Microbial signatures and innate immune gene expression in lamina Propria phagocytes of inflammatory bowel disease patients. Cell Mol Gastroenterol Hepatol, 2020, 9(3): 387-402.
50.	Peyrin-Biroulet L, Chamaillard M, Gonzalez F, et al. Mesenteric fat in Crohn's disease: a pathogenetic hallmark or an innocent bystander. Gut, 2007, 56(4): 577-583.
51.	Tsang L, Banerjee N, Tabibian JH. Bloody diarrhea and weight loss in a patient in remission from ulcerative colitis. Gastroenterology, 2019, 157(5): 1207-1209.
52.	Crook MA, Velauthar U, Moran L, et al. Hypocholesterolaemia in a hospital population. Ann Clin Biochem, 1999, 36( Pt 5): 613-616.
53.	Yalçın B, Gür G, Artüz F, et al. Prevalence of metabolic syndrome in Behçet disease: a case-control study in Turkey. Am J Clin Dermatol, 2013, 14(5): 421-425.

1. Park SB, Yoon JY, Cha JM. What are the different phenotypes of inflammatory bowel disease in Asia. Gut Liver, 2022, 16(5): 676-685.
2. Burisch J, Jess T, Martinato M, et al. The burden of inflammatory bowel disease in Europe. J Crohns Colitis, 2013, 7(4): 322-337.
3. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet, 2017, 390(10114): 2769-2778.
4. Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 56-66.
5. Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol, 2020, 20(7): 411-426.
6. Crooks B, Misra R, Arebi N, et al. The dietary practices and beliefs of British South Asian people living with inflammatory bowel disease: a multicenter study from the United Kingdom. Intest Res, 2022, 20(1): 53-63.
7. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev, 2008, 29(7): 777-822.
8. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet, 2005, 365(9468): 1415-1428.
9. Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol, 2016, 31(5): 936-944.
10. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology, 2018, 67(1): 328-357.
11. Argollo M, Gilardi D, Peyrin-Biroulet C, et al. Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol Hepatol, 2019, 4(8): 643-654.
12. Dragasevic S, Stankovic B, Kotur N, et al. Metabolic syndrome in inflammatory bowel disease: association with genetic markers of obesity and inflammation. Metab Syndr Relat Disord, 2020, 18(1): 31-38.
13. Michalak A, Mosińska P, Fichna J. Common links between metabolic syndrome and inflammatory bowel disease: current overview and future perspectives. Pharmacol Rep, 2016, 68(4): 837-846.
14. Nagahori M, Hyun SB, Totsuka T, et al. Prevalence of metabolic syndrome is comparable between inflammatory bowel disease patients and the general population. J Gastroenterol, 2010, 45(10): 1008-1013.
15. Hyun CK. Molecular and pathophysiological links between metabolic disorders and inflammatory bowel diseases. Int J Mol Sci, 2021, 22(17): 9139.
16. Chen J, Xu F, Ruan X, et al. Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses. EBioMedicine, 2023, 89: 104494.
17. Freuer D, Linseisen J, Meisinger C. Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study. BMC Med, 2022, 20(1): 82.
18. Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease. Int J Epidemiol, 2003, 32(1): 1-22.
19. Lind L. Genome-wide association study of the metabolic syndrome in UK biobank. Metab Syndr Relat Disord, 2019, 17(10): 505-511.
20. de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet, 2017, 49(2): 256-261.
21. Lai SW, Kuo YH, Liao KF. Association between inflammatory bowel disease and diabetes mellitus. Clin Gastroenterol Hepatol, 2020, 18(4): 1002-1003.
22. Cainzos-Achirica M, Glassner K, Zawahir HS, et al. Inflammatory bowel disease and atherosclerotic cardiovascular disease: JACC review topic of the week. J Am Coll Cardiol, 2020, 76(24): 2895-2905.
23. Chen B, Collen LV, Mowat C, et al. Inflammatory bowel disease and cardiovascular diseases. Am J Med, 2022, 135(12): 1453-1460.
24. Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology, 2022, 75(4): 785-796.
25. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
26. 韩昕宇, 吴天强, 冯晓玲. 孟德尔随机化研究甲状腺功能减退症与多囊卵巢综合征的因果关系. 现代预防医学, 2023, 50(16): 2881-2884,2897.
27. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
28. 于天琦, 徐文涛, 苏雅娜, 等. 孟德尔随机化研究基本原理、方法和局限性. 中国循证医学杂志, 2021, 21(10): 1227-1234.
29. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
30. Yang S, Pudasaini R, Zhi H, et al. The relationship between blood lipids and risk of atrial fibrillation: univariable and multivariable Mendelian randomization analysis. Nutrients, 2021, 14(1): 181.
31. Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol, 2020, 17(4): 223-237.
32. Jiang L, Li JC, Shen L, et al. Association between inflammatory bowel disease and Alzheimer's disease: multivariable and bidirectional Mendelian randomisation analyses. Gut, 2023, 72(9): 1797-1799.
33. Oza C, Karguppikar M, Khadilkar V, et al. A pilot study to determine association of parental metabolic syndrome with development of metabolic risk in Indian children, adolescents and youth with type-1 diabetes. Diabetes Metab Syndr, 2022, 16(4): 102453.
34. Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest, 2019, 129(10): 4001-4008.
35. Frank DM, Bradshaw PT, Mujahid M, et al. Adolescent BMI trajectory and associations with adult metabolic syndrome and offspring obesity. Obesity (Silver Spring), 2023, 31(7): 1924-1932.
36. Li Y, Gui J, Liu H, et al. Predicting metabolic syndrome by obesity- and lipid-related indices in mid-aged and elderly Chinese: a population-based cross-sectional study. Front Endocrinol (Lausanne), 2023, 14: 1201132.
37. Tsaban G. Metabolic syndrome, LDL-hypercholesterolaemia, and cerebrocardiovascular risk: sex matters. Eur J Prev Cardiol, 2022, 28(18): 2018-2020.
38. Soleimani M, Barone S, Luo H, et al. Pathogenesis of hypertension in metabolic syndrome: the role of fructose and salt. Int J Mol Sci, 2023, 24(5): 4294.
39. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol, 2010, 56(14): 1113-1132.
40. Je Y, Han K, Chun J, et al. Association of waist circumference with the risk of inflammatory bowel disease: a nationwide cohort study of 10 million individuals in Korea. J Crohns Colitis, 2023, 17(5): 681-692.
41. Chan SSM, Chen Y, Casey K, et al. Obesity is associated with increased risk of crohn's disease, but not ulcerative colitis: a pooled analysis of five prospective cohort studies. Clin Gastroenterol Hepatol, 2022, 20(5): 1048-1058.
42. Leal Vde O, Mafra D. Adipokines in obesity. Clin Chim Acta, 2013, 419: 87-94.
43. Korek E, Krauss H. Novel adipokines: their potential role in the pathogenesis of obesity and metabolic disorders. Postepy Hig Med Dosw (Online), 2015, 69: 799-810.
44. Waluga M, Hartleb M, Boryczka G, et al. Serum adipokines in inflammatory bowel disease. World J Gastroenterol, 2014, 20(22): 6912-6917.
45. Verdugo-Meza A, Ye J, Dadlani H, et al. Connecting the dots between inflammatory bowel disease and metabolic syndrome: a focus on gut-derived metabolites. Nutrients, 2020, 12(5): 1434.
46. Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol, 2012, 13(9): R79.
47. Jie Z, Xia H, Zhong SL, et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat Commun, 2017, 8(1): 845.
48. 任士萌, 梅璐, 黄煌, 等. 非酒精性脂肪性肝病患者肠道菌群及生物化学指标相关性分析. 中华肝脏病杂志, 2019, 27(5): 369-375.
49. Dheer R, Davies JM, Quintero MA, et al. Microbial signatures and innate immune gene expression in lamina Propria phagocytes of inflammatory bowel disease patients. Cell Mol Gastroenterol Hepatol, 2020, 9(3): 387-402.
50. Peyrin-Biroulet L, Chamaillard M, Gonzalez F, et al. Mesenteric fat in Crohn's disease: a pathogenetic hallmark or an innocent bystander. Gut, 2007, 56(4): 577-583.
51. Tsang L, Banerjee N, Tabibian JH. Bloody diarrhea and weight loss in a patient in remission from ulcerative colitis. Gastroenterology, 2019, 157(5): 1207-1209.
52. Crook MA, Velauthar U, Moran L, et al. Hypocholesterolaemia in a hospital population. Ann Clin Biochem, 1999, 36( Pt 5): 613-616.
53. Yalçın B, Gür G, Artüz F, et al. Prevalence of metabolic syndrome in Behçet disease: a case-control study in Turkey. Am J Clin Dermatol, 2013, 14(5): 421-425.

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Causal effect between metabolic syndrome and inflammatory bowel disease: a two-sample bidirectional Mendelian randomization study

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