Genetic Associations Between Autoimmune Diseases and the Risks of Severe Sepsis and 28-day Mortality: a Two-sample Mendelian Randomization Study

Overview

Journal Front Med (Lausanne)

Specialty General Medicine

Date 2024 Feb 12

PMID 38343642

Authors

Xin Tie

Yanjie Zhao

Jing Su

Xing Liu

Tongjuan Zou

Wanhong Yin

Affiliations

Soon will be listed here.

Abstract

Background: Autoimmune diseases exhibit heterogenous dysregulation of pro-inflammatory or anti-inflammatory cytokine expression, akin to the pathophysiology of sepsis. It is speculated that individuals with autoimmune diseases may have an increased likelihood of developing sepsis and face elevated mortality risks following septic events. However, current observational studies have not yielded consistent conclusions. This study aims to explore the causal relationship between autoimmune diseases and the risks of sepsis and mortality using Mendelian randomization (MR) analysis.

Methods: We conducted a two-sample MR study involving a European population, with 30 autoimmune diseases as the exposure factors. To assess causal relationships, we employed the inverse variance-weighted (IVW) method and used Cochran's Q test for heterogeneity, as well as the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for potential horizontal pleiotropy.

Results: Genetically predicted Crohn's disease ( = 0.067, se = 0.034, = 0.046, OR = 1.069, 95% CI = 1.001-1.141) and idiopathic thrombocytopenic ( = 0.069, se = 0.031, = 0.023, OR = 1.071, 95% CI = 1.009-1.136) were positively associated with an increased risk of sepsis in critical care. Conversely, rheumatoid arthritis ( = -0.104, se = 0.047, = 0.025, OR = 0.901, 95% CI = 0.823-0.987), ulcerative colitis ( = -0.208, se = 0.084, = 0.013, OR = 0.812, 95% CI = 0.690-0.957), and narcolepsy ( = -0.202, se = 0.092, = 0.028, OR = 0.818, 95% CI = 0.684-0.978) were associated with a reduced risk of sepsis in critical care. Moreover, Crohn's disease ( = 0.234, se = 0.067, = 0.001, OR = 1.263, 95% CI = 1.108-1.440) and idiopathic thrombocytopenic ( = 0.158, se = 0.061, = 0.009, OR = 1.171, 95% CI = 1.041-1.317) were also linked to an increased risk of 28-day mortality of sepsis in critical care. In contrast, multiple sclerosis ( = -0.261, se = 0.112, = 0.020, OR = 0.771, 95% CI = 0.619-0.960) and narcolepsy ( = -0.536, se = 0.184, = 0.003, OR = 0.585, 95% CI = 0.408-0.838) were linked to a decreased risk of 28-day mortality of sepsis in critical care.

Conclusion: This MR study identified causal associations between certain autoimmune diseases and risks of sepsis in critical care, and 28-day mortality in the European population. These findings suggest that exploring the mechanisms underlying autoimmune diseases may offer new diagnostic and therapeutic strategies for sepsis prevention and treatment.

References

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

Hartwig F, Davey Smith G, Bowden J . Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017; 46(6):1985-1998. PMC: 5837715. DOI: 10.1093/ije/dyx102. View

Krasselt M, Baerwald C, Petros S, Seifert O . Mortality of Sepsis in Patients With Rheumatoid Arthritis: A Single-Center Retrospective Analysis and Comparison With a Control Group. J Intensive Care Med. 2020; 36(7):766-774. PMC: 8165740. DOI: 10.1177/0885066620917588. 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

Sanderson E, Glymour M, Holmes M, Kang H, Morrison J, Munafo M . Mendelian randomization. Nat Rev Methods Primers. 2023; 2. PMC: 7614635. DOI: 10.1038/s43586-021-00092-5. View

Barrett O, Abramovich E, Dreiher J, Novack V, Abu-Shakra M . Short- and long-term mortality due to sepsis in patients with rheumatoid arthritis. Rheumatol Int. 2017; 37(6):1021-1026. DOI: 10.1007/s00296-017-3694-5. View

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

Hotchkiss R, Moldawer L, Opal S, Reinhart K, Turnbull I, Vincent J . Sepsis and septic shock. Nat Rev Dis Primers. 2017; 2:16045. PMC: 5538252. DOI: 10.1038/nrdp.2016.45. View

Fleischmann-Struzek C, Mellhammar L, Rose N, Cassini A, Rudd K, Schlattmann P . Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med. 2020; 46(8):1552-1562. PMC: 7381468. DOI: 10.1007/s00134-020-06151-x. View

10.

Hotchkiss R, Monneret G, Payen D . Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013; 13(12):862-74. PMC: 4077177. DOI: 10.1038/nri3552. View

11.

Noguchi T, Ishihara S, Uchino M, Ikeuchi H, Okabayashi K, Futami K . Clinical features and oncological outcomes of intestinal cancers associated with ulcerative colitis and Crohn's disease. J Gastroenterol. 2022; 58(1):14-24. DOI: 10.1007/s00535-022-01927-y. View

12.

Ramanathan S, Brilot F, Irani S, Dale R . Origins and immunopathogenesis of autoimmune central nervous system disorders. Nat Rev Neurol. 2023; 19(3):172-190. DOI: 10.1038/s41582-023-00776-4. View

13.

Reddy R, Chen G, Tekchandani P, Standiford T . Sepsis-induced immunosuppression: from bad to worse. Immunol Res. 2002; 24(3):273-87. DOI: 10.1385/IR:24:3:273. View

14.

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View

15.

Stanilova S, Karakolev Z, Dimov G, Dobreva Z, Miteva L, Slavov E . High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors. Intensive Care Med. 2005; 31(3):401-7. DOI: 10.1007/s00134-005-2575-7. View

16.

Oud L . Epidemiology and outcomes of sepsis among hospitalizations with systemic lupus erythematosus admitted to the ICU: a population-based cohort study. J Intensive Care. 2020; 8:3. PMC: 6945625. DOI: 10.1186/s40560-019-0424-y. View

17.

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

18.

Levy M, Evans L, Rhodes A . The Surviving Sepsis Campaign Bundle: 2018 Update. Crit Care Med. 2018; 46(6):997-1000. DOI: 10.1097/CCM.0000000000003119. View

19.

Colbert J, Schmidt E, Faubel S, Ginde A . Severe Sepsis Outcomes Among Hospitalizations With Inflammatory Bowel Disease. Shock. 2016; 47(2):128-131. DOI: 10.1097/SHK.0000000000000742. View

20.

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