Genetics of Circulating Inflammatory Proteins Identifies Drivers of Immune-mediated Disease Risk and Therapeutic Targets

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.

Citing Articles

Association between 91 circulating inflammatory proteins and the risk of glaucoma: A Mendelian randomization study.

Xu W, Fan Q, Meng Y, Nie Z, Sawut A, Xie S Sci Rep. 2025; 15(1):8876.

PMID: 40087334 DOI: 10.1038/s41598-025-92153-y.

The causal relationships between inflammatory cytokines, blood metabolites, and thyroid cancer: a two-step Mendelian randomization analysis.

Liu W, Sun Y, Zhang Y, Yin D Discov Oncol. 2025; 16(1):301.

PMID: 40072746 PMC: 11904021. DOI: 10.1007/s12672-025-02029-w.

Causal inference of inflammatory proteins in infertility: a Mendelian randomization study.

Chen P, Ni S, Ou-Yang L Front Endocrinol (Lausanne). 2025; 16:1448530.

PMID: 40070583 PMC: 11893426. DOI: 10.3389/fendo.2025.1448530.

The mediating role of circulating inflammatory cytokines in causal associations between plasma metabolites and asymptomatic bile duct and cholecyst calculus: A Mendelian randomization study.

Peng S, Wei Y, Huang H, Lan C, Zeng Z, Zhu G Medicine (Baltimore). 2025; 104(10):e41745.

PMID: 40068083 PMC: 11902928. DOI: 10.1097/MD.0000000000041745.

The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes.

Tokolyi A, Persyn E, Nath A, Burnham K, Marten J, Vanderstichele T Nat Genet. 2025; 57(3):616-625.

PMID: 40038547 PMC: 11906350. DOI: 10.1038/s41588-025-02096-3.

References

Hassan H, Zander A . Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta Haematol. 1996; 95(3-4):257-62. DOI: 10.1159/000203893. View

Friedrich M, Pohin M, Jackson M, Korsunsky I, Bullers S, Rue-Albrecht K . IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021; 27(11):1970-1981. PMC: 8604730. DOI: 10.1038/s41591-021-01520-5. View

Rappoport N, Simon A, Amariglio N, Rechavi G . The Duffy antigen receptor for chemokines, ACKR1,- 'Jeanne DARC' of benign neutropenia. Br J Haematol. 2018; 184(4):497-507. DOI: 10.1111/bjh.15730. View

Foley C, Staley J, Breen P, Sun B, Kirk P, Burgess S . A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits. Nat Commun. 2021; 12(1):764. PMC: 7858636. DOI: 10.1038/s41467-020-20885-8. View

Bamias G, Kaltsa G, Siakavellas S, Papaxoinis K, Zampeli E, Michopoulos S . High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis. Clin Immunol. 2010; 137(2):242-9. DOI: 10.1016/j.clim.2010.07.001. View

. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019; 365(6460). PMC: 7241648. DOI: 10.1126/science.aav7188. View

Kim D, Langmead B, Salzberg S . HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015; 12(4):357-60. PMC: 4655817. DOI: 10.1038/nmeth.3317. View

de Lange K, Moutsianas L, Lee J, Lamb C, Luo Y, Kennedy N . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017; 49(2):256-261. PMC: 5289481. DOI: 10.1038/ng.3760. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

10.

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

11.

Gregory A, Dendrou C, Attfield K, Haghikia A, Xifara D, Butter F . TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature. 2012; 488(7412):508-511. PMC: 4268493. DOI: 10.1038/nature11307. View

12.

Sun B, Maranville J, Peters J, Stacey D, Staley J, Blackshaw J . Genomic atlas of the human plasma proteome. Nature. 2018; 558(7708):73-79. PMC: 6697541. DOI: 10.1038/s41586-018-0175-2. View

13.

Pietzner M, Wheeler E, Carrasco-Zanini J, Kerrison N, Oerton E, Koprulu M . Synergistic insights into human health from aptamer- and antibody-based proteomic profiling. Nat Commun. 2021; 12(1):6822. PMC: 8613205. DOI: 10.1038/s41467-021-27164-0. View

14.

Peters J, Lyons P, Lee J, Richard A, Fortune M, Newcombe P . Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease. PLoS Genet. 2016; 12(3):e1005908. PMC: 4807835. DOI: 10.1371/journal.pgen.1005908. View

15.

. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1999; 53(3):457-65. View

16.

Zheng J, Haberland V, Baird D, Walker V, Haycock P, Hurle M . Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nat Genet. 2020; 52(10):1122-1131. PMC: 7610464. DOI: 10.1038/s41588-020-0682-6. View

17.

Massimino L, Lamparelli L, Houshyar Y, DAlessio S, Peyrin-Biroulet L, Vetrano S . The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework. Nat Comput Sci. 2024; 1(8):511-515. PMC: 10766544. DOI: 10.1038/s43588-021-00114-y. View

18.

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

19.

Enroth S, Johansson A, Bosdotter Enroth S, Gyllensten U . Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs. Nat Commun. 2014; 5:4684. PMC: 4143927. DOI: 10.1038/ncomms5684. View

20.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View