Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.
Causal relationship
Hypothyroidism
Mendelian randomization
Ulcerative colitis
Journal
BMC gastroenterology
ISSN: 1471-230X
Titre abrégé: BMC Gastroenterol
Pays: England
ID NLM: 100968547
Informations de publication
Date de publication:
30 Oct 2024
30 Oct 2024
Historique:
received:
13
06
2024
accepted:
14
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism. We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level. Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways. Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.
Identifiants
pubmed: 39478467
doi: 10.1186/s12876-024-03461-y
pii: 10.1186/s12876-024-03461-y
doi:
Substances chimiques
STAT4 Transcription Factor
0
STAT4 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
385Subventions
Organisme : National Natural Science Foundation of China
ID : 82341223
Organisme : the Youth Science Foundation of NSFC
ID : 82202844
Informations de copyright
© 2024. The Author(s).
Références
Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel J-FJTL. Ulcerative Colitis. 2016:340–1.
Addanki S, Patel K, Patel L, Smith B, Patel P, Uppalapati S et al. Thyroid Function Sleep Patterns: Syst Rev. 2024;16(6).
Shahid MA, Ashraf MA, Sharma S, Physiology. thyroid hormone. 2018.
Virili C, Stramazzo I, Santaguida MG, Bruno G, Brusca N, Capriello S, et al. Ulcerative Colitis as a Novel cause of increased need for Levothyroxine. Front Endocrinol (Lausanne). 2019. https://doi.org/10.3389/fendo.2019.00233 . 10:233. Epub 2019/05/02.
doi: 10.3389/fendo.2019.00233
pubmed: 31920967
Shizuma T. Concomitant thyroid disorders and Inflammatory Bowel Disease: A literature review. Biomed Res Int. 2016;2016:1–12. https://doi.org/10.1155/2016/5187061 .
doi: 10.1155/2016/5187061
Roberts CGP, Ladenson PWJL. Hypothyroidism. 2004;363(9411):793–803.
Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J. 2023. Epub 2023/11/08. https://doi.org/10.1093/eurheartj/ehad736 . PubMed PMID: 37935836.
Smith GD, Holmes M, Davies N, Ebrahim SJE. Mendel’s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues. 2020;35(2):99–111.
Burgess S, Thompson SG. Interpreting findings from mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377–89. https://doi.org/10.1007/s10654-017-0255-x . Epub 2017/05/21.
doi: 10.1007/s10654-017-0255-x
pubmed: 28527048
pmcid: 5506233
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7. https://doi.org/10.7554/eLife.34408 .
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25. https://doi.org/10.1093/ije/dyv080 . Epub 2015/06/08.
doi: 10.1093/ije/dyv080
pubmed: 26050253
pmcid: 4469799
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some Invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. https://doi.org/10.1002/gepi.21965 . Epub 2016/04/12.
doi: 10.1002/gepi.21965
pubmed: 27061298
pmcid: 4849733
Burgess S, Scott RA, Timpson NJ, Smith GD, Thompson SGJEJE. Using published data in mendelian randomization: a blueprint for efficient identification of causal risk factors. 2015;30(7):543–52.
Gibran H, Jie Z, Benjamin E, Wade KH, Valeriia H, Denis B et al. The MR-Base platform supports systematic causal inference across the human phenome. 2018;7:e34408-.
Gkatzionis A, Burgess S, Conti DV, Newcombe PJJSM. Bayesian variable selection with a pleiotropic loss function in Mendelian randomization. 2021.
Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innov (Camb). 2021;2(3):100141. https://doi.org/10.1016/j.xinn.2021.100141 . Epub 2021/09/25.
doi: 10.1016/j.xinn.2021.100141
Zhao J, Liu F, Bai L, Jiao Z, Meng Z, Jia B et al. Ulcerative colitis with autoimmune thyroid disease results in bilateral auricular ossificans: a case. 2024;8:100225.
Liu M, Luo P, Liu L, Wei X, Bai X, Li J et al. Immune-mediated inflammatory diseases and leukocyte telomere length: a mendelian randomization study. 2023;14:1129247.
Bullard BM, VanderVeen BN, McDonald SJ, Cardaci TD, Murphy EAJAJP-G, Physiology L. Cross talk between the gut microbiome and host immune response in ulcerative colitis: nonpharmacological strategies to improve homeostasis. 2022;323(6):G554–61.
Sun L, Kong R, Li H, Wang D, Rufo PA. The role of T follicular helper cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease. Gastroenterol Res Pract. 2021;2021:1–7. https://doi.org/10.1155/2021/9621738 .
doi: 10.1155/2021/9621738
Takeuchi T, Suzuki K, Kondo T, Yoshimoto K, Tsuzaka KJARD. CD3 ζ defects in systemic lupus erythematosus. 2012;71 Suppl 2(Suppl 2):i78.
Fantini MC, Giovanni M, Macdonald TTJIBD. New players in the cytokine orchestra of inflammatory bowel disease. 2010(11):1419–23.
Daniele Fina RC, Francesco, Pallone. Giovanni Monteleone%J Endocrine, Metabolic, Targets ID-D. Interleukin-21 (IL-21) Controls Inflammatory Pathways in the Gut. 2007;7(4):–.
Long Y, Xia C, Xu L, Liu C, Liu CJFI. The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells is Associated with Disease activity in patients with. Ulcerative Colitis. 2020;11.
Fukaura K, YoichiroOgino. HarueiIhara, EikichiNakamura, KazuhikoNishihara, YuichiroNishioka, KeiChinen, TakatoshiIwasa, TsutomuAso, AkiraGoto, AyakoHaraguchi, KazuhiroAkiho, HirotadaHarada, NaohikoOgawa, Yoshihiro %J inflammatory bowel diseases. Mucosal Profiles of Immune Molecules Related to T Helper and Regulatory T Cells Predict Future Relapse in patients with. Quiescent Ulcerative Colitis. 2019;25(6).
Li Q, Wang B, Mu K, Zhang JA. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – cytokines circuits beyond the Th1 – Th2 paradigm. J Cell Physiol. 2018;234(3):2204–16. https://doi.org/10.1002/jcp.27180 .
doi: 10.1002/jcp.27180
pubmed: 30246383
La Cava A. Tregs are regulated by cytokines: implications for autoimmunity. Autoimmun rev. 2008;8(1):83–7. https://doi.org/10.1016/j.autrev.2008.08.002 .
doi: 10.1016/j.autrev.2008.08.002
pubmed: 18771756
Boussiotis VAJNEJoM. Molecular and biochemical aspects of the PD-1 checkpoint pathway. 2016;375(18):1767–78.
Shi W, Zhang Y, Hao C, Guo X, Yang Q, Du J, et al. The significance of PD-1/PD-L1 imbalance in ulcerative colitis. PeerJ. 2023;11. https://doi.org/10.7717/peerj.15481 . Epub 2023/06/05. :e15481.
Long Y, Xia C, Sun Y, Ma Y, Liu CJIL. Increased circulating PD-1hiCXCR5- peripheral helper T cells are associated with disease severity of active ulcerative colitis patients. 2021.
Dyck L, Wilk MM, Raverdeau M, Misiak A, Boon L, Mills KHGJCI, Immunotherapy. Anti-PD-1 inhibits Foxp3 + Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. 2016;65(12):1491–8.
Maike S, Robert D, Ujjwal NJIJMS. Immune checkpoints as the Immune System regulators and potential biomarkers in HIV-1 infection. 2018;19(7):2000.
pd 1 antigen on the surface of (1).pdf>.
Sharpe AH, Pauken KEJNRI. The diverse functions of the PD1 inhibitory pathway. 2018(3).
Eberth JF, Porter J, Marotta EE, Fletcher LS, editors. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Asme International Mechanical Engineering Congress & Exposition; 2010.
Expression of costimulatory. Molecule CD80 in colonic dysplasia in ulcerative colitis: an immunosurveillance mechanism against colorectal cancer? %J Int J Colorectal Disease. 2006;21(8):776–83.
doi: 10.1007/s00384-006-0095-8