Genetically determined plasma trefoil factor-3 levels are causally associated with the risk of ulcerative colitis: a Mendelian randomization study

Bayram Toraman; Sami Fidan; Gökhan Yıldız

doi:10.18621/eurj.1285889

Research Article

Genetically determined plasma trefoil factor-3 levels are causally associated with the risk of ulcerative colitis: a Mendelian randomization study

Year 2024, Volume: 10 Issue: 1 - January 2024, 8 - 16, 04.01.2024

Bayram Toraman Sami Fidan Gökhan Yıldız

https://doi.org/10.18621/eurj.1285889

Abstract

Objectives: Ulcerative colitis (UC) is an inflammatory disease restricted to the colon's mucosal layer. UC is a complex disease with a largely unknown etiology. Mendelian Randomization (MR) is a method that uses variations in genes that have a causal effect of a modifiable exposure to the disease, in genetic epidemiological studies. Trefoil factor 3 (TFF3) is a secreted protein expressed mainly in the colonic mucosa that binds with the mucin 2 protein, forming a protective barrier for the colon mucosa from bacteria and other insults. This study aimed to identify if TFF3 levels in plasma are causally associated with UC.

Methods: We performed a two-sample MR study. For exposure instrumental variables (IVs), genetically determined TFF3 levels in plasma proteome quantitative trait locus data were obtained from the published literature. Outcome data were obtained from the GWAS catalog. The “TwoSampleMR” R package was used for MR. The statistical significance of IV effect sizes on the outcome is mainly evaluated by the inverse variance weighted (IVW) method.

Results: The IVW test showed considerable statistical significance in all analyzed outcomes except for Crohn’s disease (CD) samples. Heterogeneity and horizontal pleiotropy tests showed no significant results for MR sensitivity analysis.

Conclusions: We showed that TFF3 levels in plasma were causally associated with the risk of UC. Increased levels of TFF3 are reversely associated with the risk of UC. The absence of any causal relationship between TFF3 and CD from the same study cohort also supports our causal inference.

Keywords

Ulcerative colitis, trefoil factor-3, genome-wide association study, Mendelian randomization analysis

Thanks

We thank the researchers who made this study possible and whose original data we used.

References

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14. Järvå MA, Lingford JP, John A, Soler NM, Scott NE, Goddard-Borger ED. Trefoil factors share a lectin activity that defines their role in mucus. Nat Commun. 2020;11(1):2265. doi: 10.1038/s41467-020-16223-7.
15. Yang Y, Lin Z, Lin Q, Bei W, Guo J. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective. Cell Death Dis. 2022;13(1):62. doi: 10.1038/s41419-022-04504-6.
16. Suhre K, Arnold M, Bhagwat AM, et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun. 2017;8:14357. doi: 10.1038/ncomms14357.
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20. Ma K, Song P, Liu Z, et al. Genetic evidence suggests that depression increases the risk of erectile dysfunction: A Mendelian randomization study. Front Genet. 2022;13:1026227. doi: 10.3389/fgene.2022.1026227.
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23. Lawrance IC, Fiocchi C, Chakravarti S. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 2001;10(5):445-456. doi: 10.1093/hmg/10.5.445.
24. Ek WE, Karlsson T, Höglund J, Rask-Andersen M, Johansson Å. Causal effects of inflammatory protein biomarkers on inflammatory diseases. Sci Adv. 2021;7(50):eabl4359. doi: 10.1126/sciadv.abl4359.
25. Parisinos CA, Serghiou S, Katsoulis M, et al. Variation in interleukin 6 receptor gene associates with risk of Crohn's disease and ulcerative colitis. Gastroenterology. 2018;155(2):303-306.e2. doi: 10.1053/j.gastro.2018.05.022.
26. Nakov R. New markers in ulcerative colitis. Clin Chim Acta. 2019;497:141-146. doi: 10.1016/j.cca.2019.07.033.
27. Nakov R, Velikova T, Nakov V, Ianiro G, Gerova V, Tankova L. Serum trefoil factor 3 predicts disease activity in patients with ulcerative colitis. Eur Rev Med Pharmacol Sci. 2019;23(2):788-794. doi: 10.26355/eurrev_201901_16893.
28. Aamann L, Vestergaard EM, Grønbæk H. Trefoil factors in inflammatory bowel disease. World J Gastroenterol. 2014;20(12):3223-3230. doi: 10.3748/wjg.v20.i12.3223.
29. Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996;274(5285):262-265. doi: 10.1126/science.274.5285.262.
30. Mahmood A, Melley L, Fitzgerald AJ, Ghosh S, Playford RJ. Trial of trefoil factor 3 enemas, in combination with oral 5- aminosalicylic acid, for the treatment of mild-to-moderate leftsided ulcerative colitis. Aliment Pharmacol Ther. 2005;21(11):1357-1364. doi: 10.1111/j.1365-2036.2005.02436.x.

Year 2024, Volume: 10 Issue: 1 - January 2024, 8 - 16, 04.01.2024

Bayram Toraman Sami Fidan Gökhan Yıldız

https://doi.org/10.18621/eurj.1285889

Abstract

References

1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369(9573):1627-1640. doi: 10.1016/S0140-6736(07)60750-8.
2. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369(9573):1641-1657. doi: 10.1016/S0140-6736(07)60751-X
3. Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35(10):1075-1081. doi: 10.1080/003655200451207.
4. Tysk C, Lindberg E, Järnerot G, Flodérus-Myrhed B. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut. 1988;29(7):990-996. doi: 10.1136/gut.29.7.990.
5. Garza-Hernandez D, Sepulveda-Villegas M, Garcia-Pelaez J, et al. A systematic review and functional bioinformatics analysis of genes associated with Crohn's disease identify more than 120 related genes. BMC Genomics. 2022;23(1):302. doi: 10.1186/s12864-022-08491-y.
6. Welter D, MacArthur J, Morales J, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42:D1001-1006. doi: 10.1093/nar/gkt1229.
7. Kitsios GD, Zintzaras E. Genome-wide association studies: hypothesis-"free" or "engaged"? Transl Res. 2009;154(4):161-164. doi: 10.1016/j.trsl.2009.07.001.
8. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363(2):166-176. doi: 10.1056/NEJMra0905980.
9. Pearson TA, Manolio TA. How to interpret a genome-wide association study. JAMA. 2008;299(11):1335-1344. doi: 10.1001/jama.299.11.1335.
10. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601.
11. Gagliano Taliun SA, Evans DM. Ten simple rules for conducting a mendelian randomization study. PLoS Comput Biol. 2021;17(8):e1009238. doi: 10.1371/journal.pcbi.1009238.
12. Rasooly D, Patel CJ. Conducting a reproducible mendelian randomization analysis using the R analytic statistical environment. Curr Protoc Hum Genet. 2019;101(1):e82. doi: 10.1002/cphg.82.
13. Gött P, Beck S, Machado JC, Carneiro F, Schmitt H, Blin N. Human trefoil peptides: genomic structure in 21q22.3 and coordinated expression. Eur J Hum Genet. 1996;4(6):308-315. doi: 10.1159/000472224.
14. Järvå MA, Lingford JP, John A, Soler NM, Scott NE, Goddard-Borger ED. Trefoil factors share a lectin activity that defines their role in mucus. Nat Commun. 2020;11(1):2265. doi: 10.1038/s41467-020-16223-7.
15. Yang Y, Lin Z, Lin Q, Bei W, Guo J. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective. Cell Death Dis. 2022;13(1):62. doi: 10.1038/s41419-022-04504-6.
16. Suhre K, Arnold M, Bhagwat AM, et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun. 2017;8:14357. doi: 10.1038/ncomms14357.
17. Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31(21):3555-3557. doi: 10.1093/bioinformatics/btv402.
18. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740-752. doi: 10.1093/ije/dyq151.
19. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601.
20. Ma K, Song P, Liu Z, et al. Genetic evidence suggests that depression increases the risk of erectile dysfunction: A Mendelian randomization study. Front Genet. 2022;13:1026227. doi: 10.3389/fgene.2022.1026227.
21. Sun BB, Maranville JC, Peters JE, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73-79. doi: 10.1038/s41586-018-0175-2.
22. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986. doi: 10.1038/ng.3359.
23. Lawrance IC, Fiocchi C, Chakravarti S. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 2001;10(5):445-456. doi: 10.1093/hmg/10.5.445.
24. Ek WE, Karlsson T, Höglund J, Rask-Andersen M, Johansson Å. Causal effects of inflammatory protein biomarkers on inflammatory diseases. Sci Adv. 2021;7(50):eabl4359. doi: 10.1126/sciadv.abl4359.
25. Parisinos CA, Serghiou S, Katsoulis M, et al. Variation in interleukin 6 receptor gene associates with risk of Crohn's disease and ulcerative colitis. Gastroenterology. 2018;155(2):303-306.e2. doi: 10.1053/j.gastro.2018.05.022.
26. Nakov R. New markers in ulcerative colitis. Clin Chim Acta. 2019;497:141-146. doi: 10.1016/j.cca.2019.07.033.
27. Nakov R, Velikova T, Nakov V, Ianiro G, Gerova V, Tankova L. Serum trefoil factor 3 predicts disease activity in patients with ulcerative colitis. Eur Rev Med Pharmacol Sci. 2019;23(2):788-794. doi: 10.26355/eurrev_201901_16893.
28. Aamann L, Vestergaard EM, Grønbæk H. Trefoil factors in inflammatory bowel disease. World J Gastroenterol. 2014;20(12):3223-3230. doi: 10.3748/wjg.v20.i12.3223.
29. Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996;274(5285):262-265. doi: 10.1126/science.274.5285.262.
30. Mahmood A, Melley L, Fitzgerald AJ, Ghosh S, Playford RJ. Trial of trefoil factor 3 enemas, in combination with oral 5- aminosalicylic acid, for the treatment of mild-to-moderate leftsided ulcerative colitis. Aliment Pharmacol Ther. 2005;21(11):1357-1364. doi: 10.1111/j.1365-2036.2005.02436.x.

There are 30 citations in total.

Details

Primary Language	English
Subjects	Gastroenterology and Hepatology
Journal Section	Original Articles
Authors	Bayram Toraman 0000-0003-4500-5668 Sami Fidan 0000-0002-7412-4319 Gökhan Yıldız 0000-0002-6714-3343
Early Pub Date	September 9, 2023
Publication Date	January 4, 2024
Submission Date	April 19, 2023
Acceptance Date	July 21, 2023
Published in Issue	Year 2024 Volume: 10 Issue: 1 - January 2024

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AMA	Toraman B, Fidan S, Yıldız G. Genetically determined plasma trefoil factor-3 levels are causally associated with the risk of ulcerative colitis: a Mendelian randomization study. Eur Res J. January 2024;10(1):8-16. doi:10.18621/eurj.1285889

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