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Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study

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Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05–1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02–1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01–1.2; P = 0.03], tumor necrosis factor beta (TNF-β) [OR: 1.16; 95% CI: 1.02–1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01–1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-β, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.

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Data availability

We thank the participants and researchers for providing the publicly available summary data used in this study. The data sources and handling of these data are described in the Materials and Methods and in the Supplementary Tables. Further information is available from the corresponding author upon request.

Abbreviations

DLBCL:

Diffuse large B cell lymphoma

MR:

Mendelian randomization

IVs:

Instrumental variables

GWASs:

Genome-wide association studies

CI:

Confidence interval

IVW:

Inverse-variance weighted

MR-PRESSO:

MR-pleiotropy residual sum and outliers

OR:

Odds ratio

SNPs:

Single nucleotide polymorphisms

CXCL9:

CXC chemokine ligand 9

CXCL10:

CXC chemokine ligand 10

YFS:

Young Finns study

b-NGF:

Beta nerve growth factor

CTACK:

Cutaneous T-cell attracting chemokine

FGFBasic:

Basic fibroblast growth factor

G-CSF:

Granulocyte colony-stimulating factor

GRO-a:

Growth-regulated oncogene-a

HGF:

Hepatocyte growth factor

IFNg:

Interferon gamma

IL:

Interleukin

IP-10:

Interferon gamma-induced protein 10

MCP-1:

Monocyte chemotactic protein-1

MCP-3:

Monocyte-specific chemokine 3

M-CSF:

Macrophage colony-stimulating factor

MIF:

Macrophage-migration inhibitory factor

MIG:

Monokine induced by interferon gamma

MIP-1a:

Macrophage inflammatory protein-1a

MIP-1b:

Macrophage inflammatory protein-1b

PDGFbb:

Platelet-derived growth factor BB

RANTES:

Regulated on activation, normal T-cell expressed and secreted

SCF:

Stem cell factor

SCGFb:

Stem cell growth factor beta

SDF-1a:

Stromal cell-derived factor-1 alpha

TNFα:

Tumor necrosis factor alpha

TNFβ:

Tumor necrosis factor beta

TRAIL:

TNF-related apoptosis-inducing ligand

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors express their gratitude to the participants and investigators of the FinnGen and YFS, FINRISK studies. We also thank Figdraw (https://www.figdraw.com) for the assistance in model drawing.

Funding

This work was supported by the Youth Project Shaoxing People’s Hospital (Grant Number: 2023YB15), Medical and Health Science and Technology Project of Zhejiang Province (Grant Number: 2023RC107), Department of Health of Zhejiang Province (Grant Number: 2021KY1137), Young Innovative Talents Project of Zhejiang Health Science and Technology Plan (Grant Number: 2022RC078).

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Contributions

All authors contributed to the study conception and design. Jieni Yu, Chao Xu, and Leihua Fu designed the study, Zhijian Zhang and Lina Ding analyzed and interpreted the data, and drafted the manuscript. Li Hong, Feidan Gao and Jing Jin analyzed and interpreted the data, Jiaping Fu finished the figures, Weiying Feng and Pan Hong revised the manuscript. All author read and approved the final manuscript.

Corresponding author

Correspondence to Chao Xu.

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The authors have no relevant financial or non-financial interests to disclose.

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This study has been conducted using published studies and consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent.

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Jieni Yu and Leihua Fu are contributed equally to this work and share first authorship.

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Yu, J., Fu, L., Zhang, Z. et al. Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study. Clin Exp Med 23, 4585–4595 (2023). https://doi.org/10.1007/s10238-023-01221-y

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