Dataset Information

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

ABSTRACT: 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.

SUBMITTER: Zhao JH

PROVIDER: S-EPMC10457199 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Zhao Jing Hua JH Stacey David D Eriksson Niclas N Macdonald-Dunlop Erin E Hedman Åsa K ÅK Kalnapenkis Anette A Enroth Stefan S Cozzetto Domenico D Digby-Bell Jonathan J Marten Jonathan J Folkersen Lasse L Herder Christian C Jonsson Lina L Bergen Sarah E SE Gieger Christian C Needham Elise J EJ Surendran Praveen P Paul Dirk S DS Polasek Ozren O Thorand Barbara B Grallert Harald H Roden Michael M Võsa Urmo U Esko Tonu T Hayward Caroline C Johansson Åsa Å Gyllensten Ulf U Powell Nick N Hansson Oskar O Mattsson-Carlgren Niklas N Joshi Peter K PK Danesh John J Padyukov Leonid L Klareskog Lars L Landén Mikael M Wilson James F JF Siegbahn Agneta A Wallentin Lars L Mälarstig Anders A Butterworth Adam S AS Peters James E JE

Nature immunology 20230810 9

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 lymphotoxi ...[more]

PMID: 37563310

Similar Datasets

Project description:Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as a regulator of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers; glioblastoma; and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising, and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor-profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target. Clin Cancer Res; 23(9); 2143-53. ©2017 AACR.

Project description:PurposeThis study aimed to explore the potential causal relationship between genetically determined elevated levels of pro-inflammatory cytokines and iridocyclitis, including its subtypes: acute and subacute iridocyclitis (ASIR) and chronic iridocyclitis (CIR).MethodsA two-sample Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) summary data for inflammatory cytokines (cases, n = 14,824), iridocyclitis (IR; cases, n = 7306 and controls, n = 357,814), and its subtypes (ASIR: cases, n = 6166 and controls, n = 357,814; and CIR: cases, n = 1401 and controls, n = 357,814). The inverse variance-weighted (IVW) method served as the primary analysis method. Supplementary analytic methods included MR Egger, Weighted median, Weighted mode, and Simple mode methods. Pleiotropy and heterogeneity were evaluated using the Cochran's Q test, MR Egger intercept test, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), Bayesian colocalization analysis, and Linkage disequilibrium score regression (LDSC) analysis.ResultsGenetically predicted high levels of eotaxin, fibroblast growth factor 23 (FGF23), TNF-related apoptosis-inducing ligand (TRAIL), and Neurotrophin-3 were associated with an increased risk of IR. On the contrary, a high level of interleukin (IL)-2 was associated with a decreased risk of IR. Meanwhile, the IR subgroup analysis demonstrated that high levels of eotaxin and TRAIL were also associated with an increased risk of ASIR. High levels of cystatin D, tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and caspase 8 were associated with an increased risk of CIR. CCL20 and CDCP1 were associated with a decreased risk of CIR. Heterogeneity and pleiotropy tests demonstrated that our findings were stable and reliable.ConclusionsInflammatory cytokines are involved in the occurrence of IR and its subtypes. Further studies are warranted to elucidate the precise mechanisms of inflammatory cytokines in IR and its subtypes.Translational relevanceThe present study highlighted the role of inflammatory cytokines in the development of IR.

Dataset Information

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Publications

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets