Causal relationships between three plasma proteins and non-alcoholic fatty liver disease, mediated by Epstein-Barr virus EA-D antibody levels: a mendelian randomization study.
Epstein-Barr virus
Mediation effects
Mendelian randomization
Non-alcoholic fatty liver disease
Plasma proteins
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
27 10 2024
27 10 2024
Historique:
received:
09
07
2024
accepted:
18
10
2024
medline:
28
10
2024
pubmed:
28
10
2024
entrez:
28
10
2024
Statut:
epublish
Résumé
Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins-KNG1, MICB, and PKD2-with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications.
Identifiants
pubmed: 39463412
doi: 10.1038/s41598-024-77105-2
pii: 10.1038/s41598-024-77105-2
doi:
Substances chimiques
Blood Proteins
0
Antibodies, Viral
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25644Subventions
Organisme : National Natural Science Foundation of China
ID : 82170666
Informations de copyright
© 2024. The Author(s).
Références
Huang, D. Q., El-Serag, H. B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18 (4), 223–238 (2021).
pubmed: 33349658
doi: 10.1038/s41575-020-00381-6
Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the study of Liver diseases. Hepatology. 67 (1), 328–357 (2018).
pubmed: 28714183
doi: 10.1002/hep.29367
Foerster, F. et al. NAFLD-driven HCC: safety and efficacy of current and emerging treatment options. J. Hepatol. 76 (2), 446–457 (2022).
pubmed: 34555422
doi: 10.1016/j.jhep.2021.09.007
Younossi, Z. M. et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin. Gastroenterol. Hepatol. 19 (3), 580–589e5 (2021).
pubmed: 32531342
doi: 10.1016/j.cgh.2020.05.064
Saiman, Y., Duarte-Rojo, A. & Rinella, M. E. Fatty liver disease: diagnosis and stratification. Annu. Rev. Med. 73, 529–544 (2022).
pubmed: 34809436
doi: 10.1146/annurev-med-042220-020407
Suhre, K. et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat. Commun. 8, 14357 (2017).
pubmed: 28240269
doi: 10.1038/ncomms14357
Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16 (1), 19–34 (2017).
pubmed: 27910877
doi: 10.1038/nrd.2016.230
Indira Chandran, V. et al. Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness. Hepatology. 77 (2), 558–572 (2023).
pubmed: 35712786
doi: 10.1002/hep.32620
Qu, X. & Donnelly, R. Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in polycystic ovary syndrome. Int. J. Mol. Sci., 21(21), 8191 (2020).
Larsson, S. C., Butterworth, A. S. & Burgess, S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur. Heart J. 44 (47), 4913–4924 (2023).
pubmed: 37935836
doi: 10.1093/eurheartj/ehad736
Sheehan, N. A. et al. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med. 5 (8), e177 (2008).
pubmed: 18752343
doi: 10.1371/journal.pmed.0050177
Hakonarson, H., Gulcher, J. R. & Stefansson, K. deCODE Genet. Inc. Pharmacogenomics 4(2): 209–215. (2003).
Ferkingstad, E. et al. Large-scale integration of the plasma proteome with genetics and disease. Nat. Genet. 53 (12), 1712–1721 (2021).
pubmed: 34857953
doi: 10.1038/s41588-021-00978-w
Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 613 (7944), 508–518 (2023).
pubmed: 36653562
doi: 10.1038/s41586-022-05473-8
Butler-Laporte, G. et al. Genetic determinants of antibody-mediated Immune responses to infectious diseases agents: a genome-wide and HLA Association Study. Open. Forum Infect. Dis. 7 (11), ofaa450 (2020).
pubmed: 33204752
doi: 10.1093/ofid/ofaa450
Pierce, B. L., Ahsan, H. & Vanderweele, T. J. Power and instrument strength requirements for mendelian randomization studies using multiple genetic variants. Int. J. Epidemiol. 40 (3), 740–752 (2011).
pubmed: 20813862
doi: 10.1093/ije/dyq151
Zhang, Y. et al. The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization. Lipids Health Dis. 23 (1), 191 (2024).
pubmed: 38909247
doi: 10.1186/s12944-024-02134-9
Luo, J. et al. Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a mendelian randomization study. Geroscience. 44 (4), 2259–2270 (2022).
pubmed: 35689786
doi: 10.1007/s11357-022-00602-7
Yu, M. et al. Inflammatory biomarkers and delirium: a mendelian randomization study. Front. Aging Neurosci. 15, 1221272 (2023).
pubmed: 37649721
doi: 10.3389/fnagi.2023.1221272
Burgess, S. & Thompson, S. G. Avoiding bias from weak instruments in mendelian randomization studies. Int. J. Epidemiol. 40 (3), 755–764 (2011).
pubmed: 21414999
doi: 10.1093/ije/dyr036
Bowden, J. et al. A framework for the investigation of pleiotropy in two-sample summary data mendelian randomization. Stat. Med. 36 (11), 1783–1802 (2017).
pubmed: 28114746
doi: 10.1002/sim.7221
Bouras, E. et al. Circulating inflammatory cytokines and risk of five cancers: a mendelian randomization analysis. BMC Med. 20 (1), 3 (2022).
pubmed: 35012533
doi: 10.1186/s12916-021-02193-0
Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife 7, e34408 (2018).
Shu, M. J. et al. Migraine and ischemic stroke: a mendelian randomization study. Neurol. Ther. 11 (1), 237–246 (2022).
pubmed: 34904213
doi: 10.1007/s40120-021-00310-y
Jin, Y. et al. Causal effects and immune cell mediators between prescription analgesic use and risk of infectious diseases: a mendelian randomization study. Front. Immunol. 14, 1319127 (2023).
pubmed: 38193081
doi: 10.3389/fimmu.2023.1319127
Hemani, G., Tilling, K. & Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13 (11), e1007081 (2017).
pubmed: 29149188
doi: 10.1371/journal.pgen.1007081
Carter, A. R. et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur. J. Epidemiol. 36 (5), 465–478 (2021).
pubmed: 33961203
doi: 10.1007/s10654-021-00757-1
Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10 (6), 330–344 (2013).
pubmed: 23507799
doi: 10.1038/nrgastro.2013.41
Sveinbjornsson, G. et al. Multiomics study of nonalcoholic fatty liver disease. Nat. Genet. 54 (11), 1652–1663 (2022).
pubmed: 36280732
doi: 10.1038/s41588-022-01199-5
Sanyal, A. J. et al. Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 78 (4), 693–703 (2023).
pubmed: 36528237
doi: 10.1016/j.jhep.2022.11.029
Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5 (4), 572–578 (2023).
pubmed: 37037945
doi: 10.1038/s42255-023-00775-1
Takahashi, H. et al. Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD. Hepatol. Commun. 6 (1), 120–132 (2022).
pubmed: 34558835
doi: 10.1002/hep4.1696
Stanley, T. L. et al. Relationship of IGF-1 and IGF-binding proteins to disease severity and glycemia in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 106 (2), e520–e533 (2021).
pubmed: 33125080
doi: 10.1210/clinem/dgaa792
Duan, Y. et al. Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front. Immunol. 13, 880298 (2022).
pubmed: 35603224
doi: 10.3389/fimmu.2022.880298
Niu, L. et al. Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. Mol. Syst. Biol. 15 (3), e8793 (2019).
pubmed: 30824564
doi: 10.15252/msb.20188793
Anstee, Q. M. & Day, C. P. The genetics of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10 (11), 645–655 (2013).
pubmed: 24061205
doi: 10.1038/nrgastro.2013.182
Groh, V. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. USA. 93 (22), 12445–12450 (1996).
pubmed: 8901601
doi: 10.1073/pnas.93.22.12445
Kohga, K. et al. Serum levels of soluble major histocompatibility complex (MHC) class I-related chain A in patients with chronic liver diseases and changes during transcatheter arterial embolization for hepatocellular carcinoma. Cancer Sci. 99 (8), 1643–1649 (2008).
pubmed: 18754878
doi: 10.1111/j.1349-7006.2008.00859.x
Kahraman, A. et al. Major histocompatibility complex class I-related chains a and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology. 51 (1), 92–102 (2010).
pubmed: 19998387
doi: 10.1002/hep.23253
Kahraman, A. et al. Role of stress-induced NKG2D ligands in liver diseases. Liver Int. 32 (3), 370–382 (2012).
pubmed: 22097967
doi: 10.1111/j.1478-3231.2011.02608.x
Chavakis, T. et al. Inhibition of platelet adhesion and aggregation by a defined region (Gly-486-Lys-502) of high molecular weight kininogen. J. Biol. Chem. 277 (26), 23157–23164 (2002).
pubmed: 11970955
doi: 10.1074/jbc.M202529200
He, X. et al. Screening differential expression of serum proteins in AFP-negative HBV-related hepatocellular carcinoma using iTRAQ -MALDI-MS/MS. Neoplasma. 61 (1), 17–26 (2014).
pubmed: 24195504
doi: 10.4149/neo_2014_001
Abdel Wahab, A. H. A. et al. Identification of circulating protein biomarkers in patients with hepatocellular carcinoma concomitantly infected with chronic hepatitis C virus. Biomarkers. 22 (7), 621–628 (2017).
pubmed: 27788588
Yong, L., Guang, B. & Yan, L. Bioinformatic analysis of differentially expressed genes involved in the hepatitis B virus-associated acute liver failure. Acta Gastroenterol. Belg. 81 (2), 288–294 (2018).
pubmed: 30024701
Zhang, B. et al. An HBV susceptibility variant of KNG1 modulates the therapeutic effects of interferons α and λ1 in HBV infection by promoting MAVS lysosomal degradation. EBioMedicine. 94, 104694 (2023).
pubmed: 37442062
doi: 10.1016/j.ebiom.2023.104694
Zheng, W. et al. Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels. Nat. Commun. 9 (1), 2302 (2018).
pubmed: 29899465
doi: 10.1038/s41467-018-04586-x
Bozza, A. et al. Autosomal dominant polycystic kidney disease linked to PKD2 locus in a family with severe extrarenal manifestations. Am. J. Nephrol. 17 (5), 458–461 (1997).
pubmed: 9382166
doi: 10.1159/000169141
Tsiokas, L., Kim, S. & Ong, E. C. Cell biology of polycystin-2. Cell. Signal. 19 (3), 444–453 (2007).
pubmed: 17084592
doi: 10.1016/j.cellsig.2006.09.005
Mo, S. et al. Identification of common signature genes and pathways underlying the pathogenesis association between nonalcoholic fatty liver disease and atherosclerosis. Front. Cardiovasc. Med. 10, 1142296 (2023).
pubmed: 37063958
doi: 10.3389/fcvm.2023.1142296
Zhang, Y. et al. Effects of Epstein-Barr virus infection on liver function in children. J. Infect. Public. Health. 13 (2), 260–265 (2020).
pubmed: 31831396
doi: 10.1016/j.jiph.2019.11.009
Mao, S., Wu, L. & Shi, W. Risk prediction for liver injury in Epstein-Barr virus infection in pediatric respiratory tract infections. Ital. J. Pediatr. 49 (1), 138 (2023).
pubmed: 37821886
doi: 10.1186/s13052-023-01546-0
Melani, C., Jaffe, E. S. & Wilson, W. H. Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder. Blood. 135 (16), 1344–1352 (2020).
pubmed: 32107539
doi: 10.1182/blood.2019000933
Petrova, M. & Kamburov, V. Epstein-Barr virus: silent companion or causative agent of chronic liver disease? World J. Gastroenterol. 16 (33), 4130–4134 (2010).
pubmed: 20806428
doi: 10.3748/wjg.v16.i33.4130