Circulating inflammatory cytokines and risk of psoriasis: a two-sample Mendelian randomization study_West China Medical Journal

Authors：

REN Jiadong , SHEN Xiangting , LI Yanan , WANG Manli , LIU Bin , QIAN Yu ,  MAO Yingying

School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P. R. China;

Corresponding?author：

MAO Yingying, Email: myy@zcmu.edu.cn

Keywords：

Mendelian randomization; inflammatory proteins; psoriasis

DOI：

10.7507/1002-0179.202412178

Video：

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Objective To investigate the associations of circulating inflammatory proteins and risk of psoriasis by using a two-sample Mendelian randomization (MR) approach. Methods Based on the genome-wide association study (GWAS) of inflammatory proteins and psoriasis, genetic variants associated with circulating inflammatory proteins were selected as instrumental variables (IVs), and genetic association data of psoriasis were extracted. The inverse-variance weighted method was used as the primary MR method, with statistical power analysis conducted to evaluate the test power. MR-Egger regression, weighted median, maximum likelihood, and MR Pleiotropy RESidual Sum and Outlier (PRESSO) tests were used to evaluate the influence of horizontal pleiotropy on the MR association estimates. Additionally, as sensitivity analysis, a GWAS of psoriasis from the FinnGen database was used as a replication dataset to evaluate the robustness of the results. Results A total of 558 single nucleotide polymorphisms associated with 74 inflammatory proteins were included. After False Discovery Rate (FDR) corrections, genetically predicted circulating levels of C-X-C motif chemokine ligand 9 (CXCL9) [odds ratio (OR)=1.76, 95% confidence interval (CI) (1.46, 2.11), P=2.31×10^?9], C-C motif chemokine ligand 19 (CCL19) [OR=1.41, 95%CI (1.22, 1.62), P=2.97×10^?6], and tumor necrosis factor-beta (TNFB) [OR=1.31, 95%CI (1.13, 1.52), P=3.56×10^?4] were found to be significantly associated with an increased risk of psoriasis. Sensitivity analyses yielded similar results. Statistical power analysis indicated that the power to detect these associations was greater than 99%. Conclusion Genetically predicted circulating CXCL9, CCL19, and TNFB levels are positively associated with risk of psoriasis.

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6.	Huang X, Zhao JV. Exploring the pathways linking fasting insulin to coronary artery disease: a proteome-wide Mendelian randomization study. BMC Med, 2025, 23(1): 321.
7.	Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primers, 2022, 2: 6.
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9.	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.
10.	Tsoi LC, Stuart PE, Tian C, et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun, 2017, 8: 15382.
11.	Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 2023, 613(7944): 508-518.
12.	Kintu C, Soremekun O, Kamiza AB, et al. The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study. EBioMedicine, 2023, 90: 104537.
13.	Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med, 2021, 40(25): 5434-5452.
14.	Verbanck M, Chen C, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
15.	Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. ELife, 2018, 7: e34408.
16.	Cao Z, Wu Y, Li Q, et al. A causal relationship between childhood obesity and risk of osteoarthritis: results from a two-sample Mendelian randomization analysis. Ann Med, 2022, 54(1): 1636-1645.
17.	Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922.
18.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
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23.	Duarte GV, Boeira V, Correia T, et al. Osteopontin, CCL5 and CXCL9 are independently associated with psoriasis, regardless of the presence of obesity. Cytokine, 2015, 74(2): 287-292.
24.	He H, Bissonnette R, Wu J, et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol, 2021, 147(1): 199-212.
25.	Zhong Y, Zhang BW, Li JT, et al. Ethanol extract of herpetospermum caudigerum wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9. J Integr Med, 2023, 21(6): 584-592.
26.	Xu HT, Zheng Q, Tai ZG, et al. Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway. Phytomedicine, 2024, 128: 155412.
27.	Reschke R, Shapiro JW, Yu J, et al. Checkpoint blockade-induced dermatitis and colitis are dominated by tissue-resident memory T cells and Th1/Tc1 cytokines. Cancer Immunol Res, 2022, 10(10): 1167-1174.
28.	Kanayama Y, Torii K, Ikumi K, et al. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells. JID Innov, 2021, 1(3): 100027.
29.	Yan Y, Chen R, Wang X, et al. CCL19 and CCR7 expression, signaling pathways, and adjuvant functions in viral infection and prevention. Front Cell Dev Biol, 2019, 7: 212.
30.	Ma F, Plazyo O, Billi AC, et al. Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis. Nat Commun, 2023, 14(1): 3455.
31.	Sallusto F, Lanzavecchia A. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol Rev, 2000, 177: 134-140.
32.	Wang H, Wang C, Qin R, et al. Integrative analysis of plasma proteomics and transcriptomics reveals potential therapeutic targets for psoriasis. Biomedicines, 2025, 13(6): 1380.
33.	Gottlieb AB, Chamian F, Masud S, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol, 2005, 175(4): 2721-2729.
34.	Makos A, Kuiper JH, Kehoe O, et al. Psoriatic arthritis: review of potential biomarkers predicting response to TNF inhibitors. Inflammopharmacology, 2023, 31(1): 77-87.
35.	Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood, 2012, 119(3): 651-665.

1. Sugumaran D, Yong ACH, Stanslas J. Advances in psoriasis research: from pathogenesis to therapeutics. Life Sci, 2024, 355: 122991.
2. Damiani G, Bragazzi N L, Karimkhani AC, et al. The global, regional, and national burden of psoriasis: results and insights from the global burden of disease 2019 Study. Front Med (Lausanne), 2021, 8: 743180.
3. Griffiths C, Armstrong AW, Gudjonsson JE, et al. Psoriasis. Lancet, 2021, 397(10281): 1301-1315.
4. Kanda N. Psoriasis: pathogenesis, comorbidities, and therapy updated. Int J Mol Sci, 2021, 22(6): 2979.
5. Barrera-Ochoa CA, Fonseca-Camarillo G, Vega-Memije ME, et al. Differential expression of TOB/BTG family members in patients with plaque psoriasis: cross-sectional study. Immunol Res, 2024, 72(2): 234-241.
6. Huang X, Zhao JV. Exploring the pathways linking fasting insulin to coronary artery disease: a proteome-wide Mendelian randomization study. BMC Med, 2025, 23(1): 321.
7. Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primers, 2022, 2: 6.
8. Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J, 2023, 44(47): 4913-4924.
9. 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.
10. Tsoi LC, Stuart PE, Tian C, et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun, 2017, 8: 15382.
11. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 2023, 613(7944): 508-518.
12. Kintu C, Soremekun O, Kamiza AB, et al. The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study. EBioMedicine, 2023, 90: 104537.
13. Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med, 2021, 40(25): 5434-5452.
14. Verbanck M, Chen C, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
15. Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. ELife, 2018, 7: e34408.
16. Cao Z, Wu Y, Li Q, et al. A causal relationship between childhood obesity and risk of osteoarthritis: results from a two-sample Mendelian randomization analysis. Ann Med, 2022, 54(1): 1636-1645.
17. Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922.
18. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
19. Gan T, Hu J, Liu W, et al. Causal association between anemia and cardiovascular disease: a 2-sample bidirectional Mendelian randomization study. J Am Heart Assoc, 2023, 12(12): e029689.
20. Brion MJ, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol, 2013, 42(5): 1497-1501.
21. Zhang X, Hu X, Fang S, et al. Vascular endothelial growth factor and ischemic stroke risk: a Mendelian randomization study. Neurol Ther, 2024, 13(3): 727-737.
22. Iqbal AJ, Fisher EA, Greaves DR. Inflammation-a critical appreciation of the role of myeloid cells. Microbiol Spectr, 2016, 4(5): 10.1128/microbiolspec. MCHD-0027-2016.
23. Duarte GV, Boeira V, Correia T, et al. Osteopontin, CCL5 and CXCL9 are independently associated with psoriasis, regardless of the presence of obesity. Cytokine, 2015, 74(2): 287-292.
24. He H, Bissonnette R, Wu J, et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol, 2021, 147(1): 199-212.
25. Zhong Y, Zhang BW, Li JT, et al. Ethanol extract of herpetospermum caudigerum wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9. J Integr Med, 2023, 21(6): 584-592.
26. Xu HT, Zheng Q, Tai ZG, et al. Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway. Phytomedicine, 2024, 128: 155412.
27. Reschke R, Shapiro JW, Yu J, et al. Checkpoint blockade-induced dermatitis and colitis are dominated by tissue-resident memory T cells and Th1/Tc1 cytokines. Cancer Immunol Res, 2022, 10(10): 1167-1174.
28. Kanayama Y, Torii K, Ikumi K, et al. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells. JID Innov, 2021, 1(3): 100027.
29. Yan Y, Chen R, Wang X, et al. CCL19 and CCR7 expression, signaling pathways, and adjuvant functions in viral infection and prevention. Front Cell Dev Biol, 2019, 7: 212.
30. Ma F, Plazyo O, Billi AC, et al. Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis. Nat Commun, 2023, 14(1): 3455.
31. Sallusto F, Lanzavecchia A. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol Rev, 2000, 177: 134-140.
32. Wang H, Wang C, Qin R, et al. Integrative analysis of plasma proteomics and transcriptomics reveals potential therapeutic targets for psoriasis. Biomedicines, 2025, 13(6): 1380.
33. Gottlieb AB, Chamian F, Masud S, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol, 2005, 175(4): 2721-2729.
34. Makos A, Kuiper JH, Kehoe O, et al. Psoriatic arthritis: review of potential biomarkers predicting response to TNF inhibitors. Inflammopharmacology, 2023, 31(1): 77-87.
35. Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood, 2012, 119(3): 651-665.

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