Identifying Prioritization of Therapeutic Targets for Ankylosing Spondylitis: a Multi-omics Mendelian Randomization Study

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Dec 20

PMID 39707330

Authors

Lingyu Dai

Lan Xia

Guannan Su

Yu Gao

Qingyan Jiang

Peizeng Yang

Affiliations

Soon will be listed here.

Abstract

Background: To investigate the associations of methylation, expression, and protein quantitative trait loci (mQTL, eQTL, and pQTL) with ankylosing spondylitis (AS) and find out genetically supported drug targets for AS.

Methods: The summary-data-based Mendelian randomization (SMR) and Bayesian co-localization analysis were used to assess the potential causality between AS and relevant genes. The GWAS data obtained from the International Genetics of Ankylosing Spondylitis Consortium (IGAS) were set as the discovery stage, and the FinnGen and UK Biobank databases were used to replicate the analysis as an external validation. We further integrated the multi-omics results to screen overlapped genes at different levels. The protein-protein interaction (PPI) network and enrichment analyses were used to explore the biological effect of SMR-identified genes on AS. Drug prediction and molecular docking were used to validate the medicinal value of candidate drug targets.

Results: Based on the results of multi-omics evidence screening, we identified potential associations of TNFRSF1A, B3GNT2, ERAP1, and FCGR2A with AS at different regulatory levels. At the protein level, AIF1, TNXB, APOM, and B3GNT2 were found to be negatively associated with AS risk, whereas higher levels of FCGR2A, FCGR2B, IL12B, TNFRSF1A, and ERAP1 were associated with an increased risk of AS. The bioinformatics analyses showed that the SMR-identified genes were mainly involved in immune response. Molecular docking results displayed stable binding between predicted candidate drugs and these aforementioned proteins.

Conclusion: Our study found four AS-associated genes with multi-omics evidence and nine promising drug targets for AS, which may contribute to the understanding of the genetic mechanisms of AS and provide innovative perspectives into targeted therapy for AS.

References

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Yoo M, Shin J, Kim J, Ryall K, Lee K, Lee S . DSigDB: drug signatures database for gene set analysis. Bioinformatics. 2015; 31(18):3069-71. PMC: 4668778. DOI: 10.1093/bioinformatics/btv313. View

Zheng W, Rao S . Knowledge-based analysis of genetic associations of rheumatoid arthritis to inform studies searching for pleiotropic genes: a literature review and network analysis. Arthritis Res Ther. 2015; 17:202. PMC: 4529690. DOI: 10.1186/s13075-015-0715-1. View

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

Alkassab F, Gourh P, Tan F, McNearney T, Fischbach M, Ahn C . An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis. Rheumatology (Oxford). 2007; 46(8):1248-51. DOI: 10.1093/rheumatology/kem057. View

Tian C, Shu J, Shao W, Zhou Z, Guo H, Wang J . Efficacy and safety of IL inhibitors, TNF-α inhibitors, and JAK inhibitors in patients with ankylosing spondylitis: a systematic review and Bayesian network meta-analysis. Ann Transl Med. 2023; 11(4):178. PMC: 10009571. DOI: 10.21037/atm-23-195. View

Lee Y, Bae S, Song G . FCGR2A, FCGR3A, FCGR3B polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2015; 33(5):647-54. View

Elizondo D, Brandy N, da Silva R, Haddock N, Kacsinta A, de Moura T . Allograft Inflammatory Factor-1 Governs Hematopoietic Stem Cell Differentiation Into cDC1 and Monocyte-Derived Dendritic Cells Through IRF8 and RelB . Front Immunol. 2019; 10:173. PMC: 6375893. DOI: 10.3389/fimmu.2019.00173. View

Kimura M, Kawahito Y, Obayashi H, Ohta M, Hara H, Adachi T . A critical role for allograft inflammatory factor-1 in the pathogenesis of rheumatoid arthritis. J Immunol. 2007; 178(5):3316-22. DOI: 10.4049/jimmunol.178.5.3316. View

10.

Hao Y, Crequer-Grandhomme A, Javier N, Singh A, Chen H, Manzanillo P . Structures and mechanism of human glycosyltransferase β1,3-N-acetylglucosaminyltransferase 2 (B3GNT2), an important player in immune homeostasis. J Biol Chem. 2020; 296:100042. PMC: 7948737. DOI: 10.1074/jbc.RA120.015306. View

11.

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

12.

Farh K, Marson A, Zhu J, Kleinewietfeld M, Housley W, Beik S . Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2014; 518(7539):337-43. PMC: 4336207. DOI: 10.1038/nature13835. View

13.

Medunjanin S, Putzier M, Nothen T, Weinert S, Kahne T, Luani B . DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation. Cell Mol Life Sci. 2020; 77(20):4133-4142. PMC: 7532968. DOI: 10.1007/s00018-019-03411-y. View

14.

Wong R, Cheng-Chung Wei J, Huang C, Lee H, Chiou S, Lin S . Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol. 2011; 39(1):135-40. DOI: 10.3899/jrheum.110613. View

15.

Zhong Z, Su G, Kijlstra A, Yang P . Activation of the interleukin-23/interleukin-17 signalling pathway in autoinflammatory and autoimmune uveitis. Prog Retin Eye Res. 2020; 80:100866. DOI: 10.1016/j.preteyeres.2020.100866. View

16.

Akiyama M . Multi-omics study for interpretation of genome-wide association study. J Hum Genet. 2020; 66(1):3-10. DOI: 10.1038/s10038-020-00842-5. View

17.

Exarchou S, Lindstrom U, Askling J, Eriksson J, Forsblad-dElia H, Neovius M . The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study. Arthritis Res Ther. 2015; 17:118. PMC: 4424886. DOI: 10.1186/s13075-015-0627-0. View

18.

Piotrowska K, Sluczanowska-Glabowska S, Kurzawski M, Dziedziejko V, Kopytko P, Paczkowska E . Over-Expression of Allograft Inflammatory Factor-1 (AIF-1) in Patients with Rheumatoid Arthritis. Biomolecules. 2020; 10(7). PMC: 7407126. DOI: 10.3390/biom10071064. View

19.

Yang H, Liang Y, Chung C, Chen J, Pan W . Genome-wide gene-based association study. BMC Proc. 2009; 3 Suppl 7:S135. PMC: 2795909. DOI: 10.1186/1753-6561-3-s7-s135. View

20.

Castro-Dopico T, Dennison T, Ferdinand J, Mathews R, Fleming A, Clift D . Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis. Immunity. 2019; 50(4):1099-1114.e10. PMC: 6477154. DOI: 10.1016/j.immuni.2019.02.006. View