Skip to main content

Advertisement

SpringerLink
Log in

Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background

Primary sclerosing cholangitis (PSC) is a kind of cholestatic liver disease without effective therapies and its pathogenesis is largely unknown.

Methods

We performed the proteome-wide Mendelian randomization (MR) design to estimate the causal associations of protein levels with PSC risk. Therein, genetic associations with 4,907 plasma protein levels were extracted from a proteome-wide genome-wide association study (GWAS) with 35,559 individuals and those with PSC were obtained from the International PSC Study Group (2,871 cases and 12,019 controls) and the FinnGen study (1,491 cases and 301,383 controls). The colocalization analysis was performed to detect causal variants shared by proteins and PSC. The identified proteins were further enriched in pathways and diseases. A phenome-wide association screening was performed and potential drugs were assessed as well.

Results

The results indicated that genetically predicted plasma levels of 14 proteins were positively associated with an increased risk of PSC and 8 proteins were inversely associated with PSC risk in both PSC GWAS data sets, and they all survived in sensitivity analyses. The colocalization indicated that AIF1 (allograft inflammatory factor 1) and HLA-DQA2 (major histocompatibility complex, class II, DQ alpha 2) were shared proteins with PSC, and they should be direct targets for PSC. The phenome-wide screening suggested that variants located at AIF1 or HLA-DQA2 region were closely associated with several autoimmune diseases, such as rheumatoid arthritis, implicating the shared pathogenesis among them.

Conclusions

Our study highly pinpointed two candidate targets (AIF1 and HLA-DQA2) for PSC.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

The SNP–protein associations can be accessed via https://www.decode.com/summarydata/. The SNP–PSC associations can be accessed via https://www.ebi.ac.uk/gwas/ and https://www.finngen.fi/en.

Abbreviations

PSC:

Primary sclerosing cholangitis

MR:

Mendelian randomization

GWAS:

Genome-wide association study

AIF1 :

Allograft inflammatory factor 1

HLA-DQA2 :

Major histocompatibility complex, class II, DQ alpha 2

UDCA:

Ursodeoxycholic acid

HLA:

Human leukocyte antigen

PBC:

Primary biliary cholangitis

IBD:

Inflammatory bowel disease

SNP:

Single nucleotide polymorphism

pQTL:

Protein quantitative trait locus

IV:

Instrumental variable

PC:

Principal components

SMR:

Summary-data-based Mendelian randomization

OR:

Odds ratio

HEIDI:

Heterogeneity in dependent instrument

FDR:

False discovery rate

PP:

Posterior probability

LD:

Linkage disequilibrium

IGF2R :

Insulin-like growth factor 2 receptor

TNFRSF1B :

Tumor necrosis factor receptor superfamily, member 1B

ICOSLG :

Inducible T-cell co-stimulator ligand

EPHA2 :

Ephrin type-A receptor 2

MFGE8 :

Milk fat globule EGF and factor V/VIII domain containing

References

  1. Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet. 2018;391:2547–2559

    Article  PubMed  Google Scholar 

  2. Hasegawa S, Yoneda M, Kurita Y, Nogami A, Honda Y, Hosono K, et al. Cholestatic liver disease: current treatment strategies and new therapeutic agents. Drugs. 2021;81:1181–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Visseren T, Erler NS, Polak WG, Adam R, Karam V, Vondran FWR, et al. Recurrence of primary sclerosing cholangitis after liver transplantation—analysing the European Liver Transplant Registry and beyond. Transpl Int. 2021;34:1455–1467

    Article  PubMed  Google Scholar 

  4. Melum E, Franke A, Schramm C, Weismüller TJ, Gotthardt DN, Offner FA, et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet. 2011;43:17–19

    Article  CAS  PubMed  Google Scholar 

  5. Ji SG, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017;49:269–273

    Article  CAS  PubMed  Google Scholar 

  6. Burgess S, Mason AM, Grant AJ, Slob EAW, Gkatzionis A, Zuber V, et al. Using genetic association data to guide drug discovery and development: review of methods and applications. Am J Hum Genet. 2023;110:195–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang H, Chen L, Liu Y. A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis. Front Immunol. 2023;14:1052616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen J, Xu F, Ruan X, Sun J, Zhang Y, Zhang H, et al. Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses. EBioMedicine. 2023;89: 104494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferkingstad E, Sulem P, Atlason BA, Sveinbjornsson G, Magnusson MI, Styrmisdottir EL, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet. 2021;53:1712–1721

    Article  CAS  PubMed  Google Scholar 

  10. Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016;48:481–487

    Article  CAS  PubMed  Google Scholar 

  11. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10: e1004383

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pazoki R, Vujkovic M, Elliott J, Evangelou E, Gill D, Ghanbari M, et al. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes. Nat Commun. 2021;12:2579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Han Y, Byun J, Zhu C, Sun R, Roh JY, Cordell HJ, et al. Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis. Nat Commun. 2023;14:1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Turley P, Walters RK, Maghzian O, Okbay A, Lee JJ, Fontana MA, et al. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat Genet. 2018;50:229–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Julià A, Domènech E, Ricart E, Tortosa R, García-Sánchez V, Gisbert JP, et al. A genome-wide association study on a southern European population identifies a new Crohn’s disease susceptibility locus at RBX1-EP300. Gut. 2013;62:1440–1445

    Article  PubMed  Google Scholar 

  16. Román ID, Cano-Martínez D, Lobo MV, Fernández-Moreno MD, Hernández-Breijo B, Sacristán S, et al. Infliximab therapy reverses the increase of allograft inflammatory factor-1 in serum and colonic mucosa of rats with inflammatory bowel disease. Biomarkers. 2017;22:133–144

    Article  PubMed  Google Scholar 

  17. Elizondo DM, Brandy NZ, da Silva RL, de Moura TR, Lipscomb MW. Allograft inflammatory factor-1 in myeloid cells drives autoimmunity in type 1 diabetes. JCI Insight. 2020;5(10):e136092

  18. Chinnasamy P, Lutz SE, Riascos-Bernal DF, Jeganathan V, Casimiro I, Brosnan CF, et al. Loss of allograft inflammatory factor-1 ameliorates experimental autoimmune encephalomyelitis by limiting encephalitogenic CD4 T-cell expansion. Mol Med. 2015;21:233–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peres DS, Theisen MC, Fialho MFP, Dalenogare DP, Rodrigues P, Kudsi SQ, et al. TRPA1 involvement in depression- and anxiety-like behaviors in a progressive multiple sclerosis model in mice. Brain Res Bull. 2021;175:1–15

    Article  CAS  PubMed  Google Scholar 

  20. Churchill MJ, Cantu MA, Kasanga EA, Moore C, Salvatore MF, Meshul CK. Glatiramer acetate reverses motor dysfunction and the decrease in tyrosine hydroxylase levels in a mouse model of Parkinson’s disease. Neuroscience. 2019;414:8–27

    Article  CAS  PubMed  Google Scholar 

  21. Cao F, Souders Ii CL, Perez-Rodriguez V, Martyniuk CJ. Elucidating conserved transcriptional networks underlying pesticide exposure and Parkinson’s disease: a focus on chemicals of epidemiological relevance. Front Genet. 2018;9:701

    Article  CAS  PubMed  Google Scholar 

  22. Tong M, Dong M, de la Monte SM. Brain insulin-like growth factor and neurotrophin resistance in Parkinson’s disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimers Dis. 2009;16:585–599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet. 2013;45:670–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hong SN, Park C, Park SJ, Lee CK, Ye BD, Kim YS, et al. Deep resequencing of 131 Crohn’s disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants. Gut. 2016;65:788–796

    Article  CAS  PubMed  Google Scholar 

  25. Alarcón-Riquelme ME, Ziegler JT, Molineros J, Howard TD, Moreno-Estrada A, Sánchez-Rodríguez E, et al. Genome-wide association study in an amerindian ancestry population reveals novel systemic lupus erythematosus risk loci and the role of european admixture. Arthritis Rheumatol. 2016;68:932–943

    Article  PubMed  PubMed Central  Google Scholar 

  26. Schutt C, Mirizio E, Salgado C, Reyes-Mugica M, Wang X, Chen W, et al. Transcriptomic evaluation of juvenile localized scleroderma skin with histologic and clinical correlation. Arthritis Rheumatol. 2021;73:1921–1930

    Article  CAS  PubMed  Google Scholar 

  27. Wang M, Wu J, Lei S, Mo X. Genome-wide identification of RNA modification-related single nucleotide polymorphisms associated with rheumatoid arthritis. BMC Genomics. 2023;24:153

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357:851–862

    Article  CAS  PubMed  Google Scholar 

  29. Punia S, Juran BD, Ali AH, Schlicht EM, Moore RM, Sun Z, et al. Evaluation of circulating cell-free DNA in cholestatic liver disease using liver-specific methylation markers. BMC Gastroenterol. 2021;21:149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ponnuraj EM, Hayward AR. Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum. Clin Exp Immunol. 2002;128:416–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hedl M, Lahiri A, Ning K, Cho JH, Abraham C. Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn’s disease ICOSLG risk allele. Immunity. 2014;40:734–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Arthur B, Fouad L (2023) Risk factors of primary liver cancer initiation associated with tumour initiating cell emergence: novel targets for promising preventive therapies. eGastroenterology 1:e100010

  33. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM, Carpenter TC, et al. Eph/Ephrin signaling in injury and inflammation. Am J Pathol. 2012;181:1493–1503

    Article  CAS  PubMed  Google Scholar 

  34. Can G, Ayvaz S, Can H, Demirtas S, Aksit H, Yilmaz B, et al. The Syk inhibitor fostamatinib decreases the severity of colonic mucosal damage in a rodent model of colitis. J Crohns Colitis. 2015;9:907–917

    Article  PubMed  Google Scholar 

  35. Zhang Y, Brenner M, Yang WL, Wang P. Recombinant human MFG-E8 ameliorates colon damage in DSS- and TNBS-induced colitis in mice. Lab Invest. 2015;95:480–490

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all investigators contributing to the publicly available summary statistics.

Funding

The work is supported by the Natural Science Foundation of China (82241223, U20A20360).

Author information

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin, China

    Lanlan Chen, Yuexuan Zhao, Mingyue Li & Guoyue Lv

Authors
  1. Lanlan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuexuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingyue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guoyue Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GL and LC proposed and designed the research. LC undertook data collection and performed the main data analysis. LC wrote the draft of the manuscript. YZ supervised the statistical analysis and revised the manuscript. ML visualized the results and revised the manuscript. GL supervised the whole research and claimed the integrity of data analysis.

Corresponding author

Correspondence to Guoyue Lv.

Ethics declarations

Conflict of interest

Lanlan Chen, Yuexuan Zhao, Mingyue Li, Guoyue Lv declared that no potential conflicts of interest should be disclosed in this study.

Ethical approval

Each study has been approved by its corresponding Ethical Review Committee.

Consent to participate

The public data can be accessed without restriction if not attempting to identify individual-level information.

Consent for publication

Each author has given his/her consent to publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 112 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, L., Zhao, Y., Li, M. et al. Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis. Hepatol Int 18, 517–528 (2024). https://doi.org/10.1007/s12072-023-10608-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-023-10608-8

Keywords

Search

Navigation