Unraveling Genetic Threads: Identifying Novel Therapeutic Targets for Allergic Rhinitis Through Mendelian Randomization

Overview

Journal World Allergy Organ J

Specialty Allergy & Immunology

Date 2024 Jul 23

PMID 39040085

Authors

Xuerong Huang

Ruoyi Shen

Zhi Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Allergic rhinitis (AR) is a pervasive global health issue, and currently, there is a scarcity of targeted drug therapies available. This study aims to identify potential druggable target genes for AR using Mendelian randomization (MR) analysis.

Methods: MR analysis was conducted to assess the causal effect of expression quantitative trait loci (eQTL) in the blood on AR. Data on AR were collected from 2 datasets: FinnGen(R9) (11,009 cases and 359,149 controls) and UK Biobank (25,486 cases and 87,097 controls). Colocalization analysis was utilized to assess the common causal genetic variations between the identified drug target genes and AR. We also employed available genome-wide association studies (GWAS) data to gauge the impact of druggable genes on AR biomarkers and other allergic diseases.

Results: This study employs MR to analyze the relationship between 3410 druggable genes and AR. After Bonferroni correction, 10 genes were found to be significantly associated with AR risk (). Colocalization analysis revealed a significant causal relationship between the expression variation of CFL1 and EFEMP2 genes and AR, sharing direct causal variants (colocalization probability PP.H3 + PP.H4 > 0.8), highlighting their importance as potential therapeutic targets for AR. The CFL1 gene showed a causal link with levels of thymic stromal lymphopoietin (TSLP), eosinophil count, and interleukin-13 (IL-13) (, respectively). EFEMP2 was also causally related to eosinophil count, IL-13, and interleukin-17 (IL-17) (, respectively). PheWAS analysis revealed significant associations of CFL1 with asthma, whereas EFEMP2 showed associations with both asthma and eczema. Protein-Protein Interaction (PPI) network analysis further unveiled the direct interactions of EFEMP2 and CFL1 with proteins related to immune regulation and inflammatory responses, with 77.64% of the network consisting of direct bindings, indicating their key roles in modulating AR-related immune and inflammatory responses. Notably, there was an 8.01% significant correlation between immune-related pathways and genes involved in inflammatory responses.

Conclusion: These genes present notable associations with AR biomarkers and other autoimmune diseases, offering valuable targets for developing new AR therapies.

Citing Articles

Proteome-wide Mendelian randomization and therapeutic targets for bladder cancer.

Wu M, Zhang M, Hu X, Fan H BMC Urol. 2024; 24(1):273.

PMID: 39707285 PMC: 11662591. DOI: 10.1186/s12894-024-01677-4.

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

Elias M, Long H, Newman C, Wilson P, West A, McGill P . Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. J Allergy Clin Immunol. 2017; 140(5):1299-1309. PMC: 5667587. DOI: 10.1016/j.jaci.2017.01.039. View

Zhang M, Ao T, Cheng L . Highlights of the treatment of allergic rhinitis according to Chinese guidelines. Curr Opin Allergy Clin Immunol. 2023; 23(4):334-340. DOI: 10.1097/ACI.0000000000000921. View

Finan C, Gaulton A, Kruger F, Lumbers R, Shah T, Engmann J . The druggable genome and support for target identification and validation in drug development. Sci Transl Med. 2017; 9(383). PMC: 6321762. DOI: 10.1126/scitranslmed.aag1166. View

Diaz-Ortiz M, Seo Y, Posavi M, Carceles Cordon M, Clark E, Jain N . GPNMB confers risk for Parkinson's disease through interaction with α-synuclein. Science. 2022; 377(6608):eabk0637. PMC: 9870036. DOI: 10.1126/science.abk0637. View

Xu X, Liu X, Li J, Deng X, Dai T, Ji Q . Environmental Risk Factors, Protective Factors, and Biomarkers for Allergic Rhinitis: A Systematic Umbrella Review of the Evidence. Clin Rev Allergy Immunol. 2023; 65(2):188-205. PMC: 10567804. DOI: 10.1007/s12016-023-08964-2. View

Warde-Farley D, Donaldson S, Comes O, Zuberi K, Badrawi R, Chao P . The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010; 38(Web Server issue):W214-20. PMC: 2896186. DOI: 10.1093/nar/gkq537. View

Vashisht P, Casale T . Omalizumab for treatment of allergic rhinitis. Expert Opin Biol Ther. 2013; 13(6):933-45. DOI: 10.1517/14712598.2013.795943. View

Soliai M, Kato A, Helling B, Stanhope C, Norton J, Naughton K . Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus. Genome Med. 2021; 13(1):157. PMC: 8504130. DOI: 10.1186/s13073-021-00967-y. View

10.

Gaziano L, Giambartolomei C, Pereira A, Gaulton A, Posner D, Swanson S . Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat Med. 2021; 27(4):668-676. PMC: 7612986. DOI: 10.1038/s41591-021-01310-z. View

11.

Bastarache L, Denny J, Roden D . Phenome-Wide Association Studies. JAMA. 2022; 327(1):75-76. PMC: 8880207. DOI: 10.1001/jama.2021.20356. View

12.

Luo W, Obeidat M, Di Narzo A, Chen R, Sin D, Pare P . Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases. Am J Respir Cell Mol Biol. 2015; 54(2):177-87. PMC: 4821039. DOI: 10.1165/rcmb.2014-0381OC. View

13.

Chen Y, Xu X, Wang L, Li K, Sun Y, Xiao L . Genetic insights into therapeutic targets for aortic aneurysms: A Mendelian randomization study. EBioMedicine. 2022; 83:104199. PMC: 9385553. DOI: 10.1016/j.ebiom.2022.104199. View

14.

Vosa U, Claringbould A, Westra H, Bonder M, Deelen P, Zeng B . Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021; 53(9):1300-1310. PMC: 8432599. DOI: 10.1038/s41588-021-00913-z. View

15.

Jakwerth C, Ordovas-Montanes J, Blank S, Schmidt-Weber C, Zissler U . Role of Respiratory Epithelial Cells in Allergic Diseases. Cells. 2022; 11(9). PMC: 9105716. DOI: 10.3390/cells11091387. View

16.

Lei Y, Guo P, An J, Guo C, Lu F, Liu M . Identification of pathogenic genes and upstream regulators in allergic rhinitis. Int J Pediatr Otorhinolaryngol. 2018; 115:97-103. DOI: 10.1016/j.ijporl.2018.09.005. View

17.

Schmidt A, Finan C, Gordillo-Maranon M, Asselbergs F, Freitag D, Patel R . Genetic drug target validation using Mendelian randomisation. Nat Commun. 2020; 11(1):3255. PMC: 7320010. DOI: 10.1038/s41467-020-16969-0. View

18.

Duckworth A, Gibbons M, Allen R, Almond H, Beaumont R, Wood A . Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. Lancet Respir Med. 2020; 9(3):285-294. DOI: 10.1016/S2213-2600(20)30364-7. View

19.

Freshour S, Kiwala S, Cotto K, Coffman A, McMichael J, Song J . Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res. 2020; 49(D1):D1144-D1151. PMC: 7778926. DOI: 10.1093/nar/gkaa1084. View

20.

Ogulur I, Pat Y, Ardicli O, Barletta E, Cevhertas L, Fernandez-Santamaria R . Advances and highlights in biomarkers of allergic diseases. Allergy. 2021; 76(12):3659-3686. PMC: 9292545. DOI: 10.1111/all.15089. View