Comprehensive Causal Analysis Between Autoimmune Diseases and Glioma: A Mendelian Randomization Study

Overview

Journal Medicine (Baltimore)

Specialty General Medicine

Date 2025 Mar 11

PMID 40068088

Authors

Ni Deng

Rafeq Agila

Qiang He

Chao You

Songping Zheng

Affiliations

Soon will be listed here.

Abstract

The causal association between the autoimmune disease and the development of glioma and its subtypes remains unclear. We performed a comprehensive Mendelian randomization (MR) to clarify their causal association from genetic perspective. We obtained the summary-level datasets for autoimmune diseases from recently published genome-wide association studies in the UK Biobank (UKB) and the FinnGen consortium. Additionally, we collected summary statistics datasets related to glioma and its subtypes from a comprehensive meta-analysis genome-wide association study, which included 12,488 cases and 18,169 controls. We primarily used inverse variance weighting method, supplemented by Bonferroni correction to account for multiple tests to reduce the probability of false positive results. We also performed sensitivity analyses to address potential pleiotropy and strengthen the reliability of the results. After meta-analysis, pernicious anemia may decrease the risk of glioblastoma (GBM) (UKB: odds ratio (OR) = 0.01, 95% confidence interval (CI) = 0.01-0.02, P = 1.01E-12; FinnGen: OR = 0.86, 95% CI = 0.79-0.93, P = .0002; Meta: OR = 0.04, 95% CI = 0.03-0.04). In reverse MR analysis, GBM decreased the risk of celiac disease (UKB: OR = 0.96, 95% CI = 0.95-0.98, P = .0000; FinnGen: OR = 0.89, 95% CI = 0.84-0.94, P = .0001; Meta: OR = 0.95, 95% CI = 0.94-0.97). Heterogeneity and pleiotropy analyses, and reverse analysis, confirmed the robustness of these results. From the genetic perspective, our MR study uncovered that pernicious anemia may decrease the risk of GBM. Conversely, GBM appeared to mitigate the risk of celiac disease. Future studies are required to validate the causal association and illuminate the underlying mechanisms.

References

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

Pierce B, Burgess S . Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013; 178(7):1177-84. PMC: 3783091. DOI: 10.1093/aje/kwt084. View

Zhao Q, Chen Y, Wang J, Small D . Powerful three-sample genome-wide design and robust statistical inference in summary-data Mendelian randomization. Int J Epidemiol. 2019; 48(5):1478-1492. DOI: 10.1093/ije/dyz142. View

Touat M, Idbaih A, Sanson M, Ligon K . Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017; 28(7):1457-1472. PMC: 5834086. DOI: 10.1093/annonc/mdx106. View

Cordell H, Han Y, Mells G, Li Y, Hirschfield G, Greene C . International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015; 6:8019. PMC: 4580981. DOI: 10.1038/ncomms9019. View

Dendrou C, Petersen J, Rossjohn J, Fugger L . HLA variation and disease. Nat Rev Immunol. 2018; 18(5):325-339. DOI: 10.1038/nri.2017.143. View

Bentham J, Morris D, Cunninghame Graham D, Pinder C, Tombleson P, Behrens T . Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015; 47(12):1457-1464. PMC: 4668589. DOI: 10.1038/ng.3434. View

Ha E, Bae S, Kim K . Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2020; 80(5):558-565. PMC: 8053349. DOI: 10.1136/annrheumdis-2020-219065. View

Green R, Allen L, Bjorke-Monsen A, Brito A, Gueant J, Miller J . Vitamin B deficiency. Nat Rev Dis Primers. 2017; 3:17040. DOI: 10.1038/nrdp.2017.40. View

10.

Lopez-Isac E, Acosta-Herrera M, Kerick M, Assassi S, Satpathy A, Granja J . GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun. 2019; 10(1):4955. PMC: 6823490. DOI: 10.1038/s41467-019-12760-y. View

11.

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

12.

Ye C, Kong L, Wang Y, Dou C, Zheng J, Xu M . Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans. Nat Hum Behav. 2023; 7(8):1357-1370. DOI: 10.1038/s41562-023-01646-1. View

13.

Wang D, Ayers M, Catmull D, Hazelwood L, Bernard C, Orian J . Astrocyte-associated axonal damage in pre-onset stages of experimental autoimmune encephalomyelitis. Glia. 2005; 51(3):235-40. DOI: 10.1002/glia.20199. View

14.

Wang L, Wang F, Gershwin M . Human autoimmune diseases: a comprehensive update. J Intern Med. 2015; 278(4):369-95. DOI: 10.1111/joim.12395. View

15.

Hemminki K, Forsti A, Fallah M, Sundquist J, Sundquist K, Ji J . Risk of cancer in patients with medically diagnosed hay fever or allergic rhinitis. Int J Cancer. 2014; 135(10):2397-403. DOI: 10.1002/ijc.28873. View

16.

Tsoi L, Spain S, Knight J, Ellinghaus E, Stuart P, Capon F . Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012; 44(12):1341-8. PMC: 3510312. DOI: 10.1038/ng.2467. View

17.

Chen L, Yang H, Li H, He C, Yang L, Lv G . Insights into modifiable risk factors of cholelithiasis: A Mendelian randomization study. Hepatology. 2021; 75(4):785-796. PMC: 9300195. DOI: 10.1002/hep.32183. View

18.

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

19.

Skrivankova V, Richmond R, Woolf B, Davies N, Swanson S, VanderWeele T . Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021; 375:n2233. PMC: 8546498. DOI: 10.1136/bmj.n2233. View

20.

Beecham A, Patsopoulos N, Xifara D, Davis M, Kemppinen A, Cotsapas C . Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013; 45(11):1353-60. PMC: 3832895. DOI: 10.1038/ng.2770. View