Causal relationship between 91 inflammatory factors and lung cancer: A Mendelian randomization study_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

FAN Qinglu , NIE Zhihao , WEI Shujian , LUO Renwei ,  XIE Songping

Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China;

Corresponding author：

XIE Songping, Email: songping0428@126.com

Keywords：

Inflammatory cytokines; lung cancer; Mendelian randomization; causal relationship

DOI：

10.7507/1007-4848.202403005

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To explore the potential causal relationship between 91 inflammatory factors and the risk of lung cancer (LC). Methods By extracting related data of inflammatory factors and LC and its subtypes from public databases of genome-wide association studies (GWAS), bidirectional, repeated, multivariable Mendelian randomization (MR) and subgroup MR methods were used for analysis. The inverse variance weighted method was mainly used for causal inference, and a series of sensitivity analyses were applied to verify the strength of the results. Results Higher levels of CD5, interleukin-18 (IL-18), and oncostatin-M (OSM) were causally associated with a lower risk of LC, while nerve growth factor-β (NGF-β) and S100 calcium-binding protein A12 (S100A12) were associated with an increased risk of LC. Subgroup MR analysis results showed that IL-18 had a causal relationship with a reduced risk of lung adenocarcinoma, while NGF-β and S100A12 had a causal relationship with an increased risk of lung adenocarcinoma; CD5 and OSM had a causal relationship with a reduced risk of lung squamous cell carcinoma; NGF-β had a causal relationship with an increased risk of small cell lung cancer. Conclusion Five inflammatory factors, including CD5, IL-18, OSM, NGF-β, and S100A12 have a causal correlation with the risk of LC, providing potential targets for early screening of LC patients and development of therapeutic drugs.

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1. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
2. Zhao D, Lu J, Zeng W, et al. Changing trends in disease burden of lung cancer in China from 1990-2019 and following 15-year prediction. Curr Probl Cancer, 2024, 48: 101036.
3. Wang Y, Lei H, Li X, et al. Lung cancer-specific mortality risk and public health insurance: A prospective cohort study in Chongqing, Southwest China. Front Public Health, 2022, 10: 842844.
4. Li K, Cao X, Ai B, et al. Salvage surgery following downstaging of advanced non-small cell lung cancer by targeted therapy. Thorac Cancer, 2021, 12(15): 2161-2169.
5. 牛涛, 周逢海. 炎症与肿瘤微环境. 中南大学学报(医学版), 2023, 48(12): 1899-1913.
6. Chimenz R, Tropeano A, Chirico V, et al. IL-17 serum level in patients with chronic mucocutaneous candidiasis disease. Pediatr Allergy Immunol, 2022, 33(Suppl 27): 77-79.
7. Diem S, Schmid S, Krapf M, et al. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer, 2017, 111: 176-181.
8. Zheng H, Liu JF. Studies on the relationship between P13K/AKT signal pathway-mediated MMP-9 gene and lung cancer. Eur Rev Med Pharmacol Sci, 2017, 21(4): 753-759.
9. Memarzia A, Saadat S, Asgharzadeh F, et al. Therapeutic effects of medicinal plants and their constituents on lung cancer, in vitro, in vivo and clinical evidence. J Cell Mol Med, 2023, 27(19): 2841-2863.
10. Sun J, Chen X, Wang Y. Comparison of the diagnostic value of CEA combined with OPN or DKK1 in non-small cell lung cancer. Oncol Lett, 2020, 20(3): 3046-3052.
11. Fu Y, Zhang Y, Lei Z, et al. Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer. J Hematol Oncol, 2020, 13(1): 169.
12. 韩珊珊, 路洋, 刘寨东. 薏苡仁化学成分及抗肿瘤作用研究进展. 中华中医药学刊, 2024. Epub ahead of print.
13. Li S, Xu Y, Zhang Y, et al. Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer. NPJ Precis Oncol, 2020, 4: 25.
14. Wu K, Sun Q, Liu D, et al. Genetically predicted circulating levels of cytokines and the risk of oral cavity and pharyngeal cancer: A bidirectional mendelian-randomization study. Front Genet, 2024, 14: 1321484.
15. Kong Y, Wang X, Xu H, et al. A Mendelian randomization study on the causal association of circulating cytokines with colorectal cancer. PLoS One, 2023, 18(12): e0296017.
16. Li BH, Yan SY, Luo LS, et al. Ten interleukins and risk of prostate cancer. Front Oncol, 2023, 13: 1108633.
17. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
18. Davey Smith G, Hemani G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-R98.
19. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: A blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
20. Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol, 2023, 24(9): 1540-1551.
21. McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet, 2017, 49(7): 1126-1132.
22. Elsworth BL, Lyon MS, Alexander T, et al. The MRC IEU OpenGWAS data infrastructure. bioRxiv, 2020. DOI:10.1101/2020.08.10.244293.
23. Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: A review of the approaches used and the quality of reporting. Int J Epidemiol, 2015, 44(2): 496-511.
24. Shi Q, Wang Q, Wang Z, et al. Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study. Front Immunol, 2023, 14: 1088778.
25. Zhong S, Yang W, Zhang Z, et al. Association between viral infections and glioma risk: A two-sample bidirectional Mendelian randomization analysis. BMC Med, 2023, 21(1): 487.
26. Fan Q, Meng Y, Nie Z, et al. Sex hormone-binding globulin exerts sex-related causal effects on lower extremity varicose veins: Evidence from gender-stratified Mendelian randomization. Front Endocrinol (Lausanne), 2023, 14: 1230955.
27. Meng Y, Tan Z, Liu C, et al. Association between inflammatory bowel disease and iridocyclitis: A Mendelian randomization study. J Clin Med, 2023, 12(4): 1282.
28. Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: A Mendelian randomization study. Hepatology, 2022, 75(4): 785-796.
29. Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: An expanded tool for searching human genotype-phenotype associations. Bioinformatics, 2019, 35(22): 4851-4853.
30. Bowden J, Del Greco M F, Minelli C, et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: The role of the I2 statistic. Int J Epidemiol, 2016, 45(6): 1961-1974.
31. Yuan S, Wang L, Sun J, et al. Genetically predicted sex hormone levels and health outcomes: Phenome-wide Mendelian randomization investigation. Int J Epidemiol, 2022, 51(6): 1931-1942.
32. Bowden J, Spiller W, Del Greco M F, et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int J Epidemiol, 2018, 47(4): 1264-1278.
33. Zhang Q, Zhang X, Zhang J, et al. Causal relationship between lung function and atrial fibrillation: A two sample univariable and multivariable, bidirectional Mendelian randomization study. Front Cardiovasc Med, 2021, 8: 769198.
34. Liu C, Chen Y, Zhang Z, et al. Iron status and NAFLD among European populations: A bidirectional two-sample Mendelian randomization study. Nutrients, 2022, 14(24): 5237.
35. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet, 2018, 27(R2): R195-R208.
36. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
37. Chen X, Hong X, Gao W, et al. Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: A Mendelian randomization study. J Transl Med, 2022, 20(1): 216.
38. Su Y, Hu Y, Xu Y, et al. Genetic causal relationship between age at menarche and benign oesophageal neoplasia identified by a Mendelian randomization study. Front Endocrinol (Lausanne), 2023, 14: 1113765.
39. Yang M, Xu J, Zhang F, et al. Large-scale genetic correlation analysis between spondyloarthritis and human blood metabolites. J Clin Med, 2023, 12(3): 1201.
40. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: A two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
41. Wang Z, Li S, Tan D, et al. Association between inflammatory bowel disease and periodontitis: A bidirectional two-sample Mendelian randomization study. J Clin Periodontol, 2023, 50(6): 736-743.
42. Levi-Montalcini R. The nerve growth factor 35 years later. Science, 1987, 237(4819): 1154-1162.
43. Wang J, Chen Y, Li X, et al. Perineural invasion and associated pain transmission in pancreatic cancer. Cancers (Basel), 2021, 13(18): 4594.
44. Jung HH, Kim JY, Cho EY, et al. Elevated level of nerve growth factor (NGF) in serum-derived exosomes predicts poor survival in patients with breast cancer undergoing neoadjuvant chemotherapy. Cancers (Basel), 2021, 13(21): 5260.
45. 雪克来提·库尔班, 阿米娜·阿不都热合曼, 艾力·赛丁. 三阴性乳腺癌患者血清前列腺特异抗原和神经生长因子表达与骨转移发生的相关性. 中华实用诊断与治疗杂志, 2021, 35(8): 767-770.
46. Liu P, Li S, Tang L. Nerve growth factor: A potential therapeutic target for lung diseases. Int J Mol Sci, 2021, 22(17): 9112.
47. Gao F, Griffin N, Faulkner S, et al. The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung. Sci Rep, 2018, 8(1): 8135.
48. He M, Roussak K, Ma F, et al. CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses. Science, 2023, 379(6633): eabg2752.
49. 贺欣, 邢莉民, 邵宗鸿. CD5及其在自身免疫性疾病中的作用研究进展. 中国免疫学杂志, 2020, 36(14): 1766-1770.
50. Yoshizaki A, Miyagaki T, DiLillo DJ, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature, 2012, 491(7423): 264-268.
51. Moreno-Manuel A, Jantus-Lewintre E, Simões I, et al. CD5 and CD6 as immunoregulatory biomarkers in non-small cell lung cancer. Transl Lung Cancer Res, 2020, 9(4): 1074-1083.
52. 武鑫鑫, 陶李, 杨媛媛, 等. S100A12蛋白在自身免疫性疾病中的研究进展. 中国免疫学杂志, 2020, 36(22): 2797-2801.
53. Šumová B, Cerezo LA, Szczuková L, et al. Circulating S100 proteins effectively discriminate SLE patients from healthy controls: A cross-sectional study. Rheumatol Int, 2019, 39(3): 469-478.
54. Kim K, Kim HJ, Binas B, et al. Inflammatory mediators ATP and S100A12 activate the NLRP3 inflammasome to induce MUC5AC production in airway epithelial cells. Biochem Biophys Res Commun, 2018, 503(2): 657-664.
55. Qi C, Sun SW, Xiong XZ. From COPD to lung cancer: Mechanisms linking, diagnosis, treatment, and prognosis. Int J Chron Obstruct Pulmon Dis, 2022, 17: 2603-2621.
56. Li J, Li J, Hao H, et al. Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma. BMC Cancer, 2023, 23(1): 110.
57. Forder A, Zhuang R, Souza VGP, et al. Mechanisms contributing to the comorbidity of COPD and lung cancer. Int J Mol Sci, 2023, 24(3): 2859.
58. 卫会明, 郑蕾, 魏世杰, 等. 皮瓣修复术后早期感染血浆NLRP3炎症小体-IL-1β信号通路的表达. 中华医院感染学杂志, 2022, 32(13): 1996-2000.
59. Xu L, Li K, Li J, et al. IL-18 serves as a main effector of CAF-derived METTL3 against immunosuppression of NSCLC via driving NF-κB pathway. Epigenetics, 2023, 18(1): 2265625.
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