Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427-0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006-1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002-0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001-0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

Keywords

myeloproliferative neoplasms / inflammatory regulators / bidirectional Mendelian randomization

References

[1] Nangalia J, Green AR. Myeloproliferative neoplasms: from origins to outcomes. Blood 2017; 130(23) 2475-2483

[2] Silvennoinen O, Hubbard SR. Molecular insights into regulation of JAK2 in myeloproliferative neoplasms. Blood 2015; 125(22) 3388-3392

[3] Venugopal S, Mascarenhas J. Novel therapeutics in myeloproliferative neoplasms. J Hematol Oncol 2020; 13(01) 162

[4] Bogeska R, Mikecin AM, Kaschutnig P.et al. Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 2022; 29 (08) 1273-1284.e8

[5] Omer-Javed A, Pedrazzani G, Albano L.et al. Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells. Cell 2022; 185 (13) 2248-2264.e21

[6] Greenfield G, McMullin MF, Mills K. Molecular pathogenesis of the myeloproliferative neoplasms. J Hematol Oncol 2021; 14(01) 103

[7] Bjørn ME, Hasselbalch HC. The role of reactive oxygen species in myelofibrosis and related neoplasms. Mediators Inflamm 2015; 2015: 648090

[8] Kleppe M, Koche R, Zou L.et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell 2018; 33 (01) 29-43.e7

[9] Luque Paz D, Kralovics R, Skoda RC. Genetic basis and molecular profiling in myeloproliferative neoplasms. Blood 2023; 141(16) 1909-1921

[10] Marinaccio C, Suraneni P, Celik H.et al. LKB1/STK11 is a tumor suppressor in the progression of myeloproliferative neoplasms. Cancer Discov 2021; 11(06) 1398-1410

[11] Mazza GL, Mead-Harvey C, Mascarenhas J.et al; Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 trial teams. Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials. Lancet Haematol 2022; 9(01) e38-e48

[12] Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014; 23(R1): R89-R98

[13] Choi KW, Chen CY, Stein MB.et al; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry 2019; 76(04) 399-408

[14] Ligthart S, Vaez A, Võsa U.et al; LifeLines Cohort Study, ; CHARGE Inflammation Working Group. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am J Hum Genet 2018; 103(05) 691-706

[15] Ahola-Olli AV, Würtz P, Havulinna AS.et al. Genome-wide association study identifies 27 loci influencing concentrations of circulating cytokines and growth factors. Am J Hum Genet 2017; 100(01) 40-50

[16] Bao EL, Nandakumar SK, Liao X.et al; FinnGen, ; 23andMe Research Team. Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells. Nature 2020; 586(7831) 769-775

[17] Bowden J, Del Greco M F, Minelli C, Davey Smith G, Sheehan NA, Thompson JR. 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(06) 1961-1974

[18] Wang Q, Shi Q, Lu J, Wang Z, Hou J. Causal relationships between inflammatory factors and multiple myeloma: a bidirectional Mendelian randomization study. Int J Cancer 2022; 151(10) 1750-1759

[19] Yu Z, Coresh J, Qi G.et al. A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure. Kidney Int 2020; 98(03) 708-716

[20] 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(02) 512-525

[21] Freeman G, Cowling BJ, Schooling CM. Power and sample size calculations for Mendelian randomization studies using one genetic instrument. Int J Epidemiol 2013; 42(04) 1157-1163

[22] Abu-Zeinah G, Di Giandomenico S, Choi D.et al. Hematopoietic fitness of JAK2V617F myeloproliferative neoplasms is linked to clinical outcome. Blood Adv 2022; 6(18) 5477-5481

[23] Risum M, Madelung A, Bondo H.et al. The JAK2V617F allele burden and STAT3- and STAT5 phosphorylation in myeloproliferative neoplasms: early prefibrotic myelofibrosis compared with essential thrombocythemia, polycythemia vera and myelofibrosis. APMIS 2011; 119(08) 498-504

[24] Kleppe M, Kwak M, Koppikar P.et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov 2015; 5(03) 316-331

[25] Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol 2011; 29(10) 1356-1363

[26] Øbro NF, Grinfeld J, Belmonte M.et al. Longitudinal cytokine profiling identifies GRO-α and EGF as potential biomarkers of disease progression in essential thrombocythemia. HemaSphere 2020; 4(03) e371

[27] Rosmarin D, Passeron T, Pandya AG.et al; TRuE-V Study Group. Two phase 3, randomized, controlled trials of ruxolitinib cream for vitiligo. N Engl J Med 2022; 387(16) 1445-1455

[28] Barbui T, Carobbio A, Finazzi G.et al; AGIMM and IIC Investigators. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica 2011; 96(02) 315-318

[29] Assis DN, Takahashi H, Leng L, Zeniya M, Boyer JL, Bucala R. A macrophage migration inhibitory factor polymorphism is associated with autoimmune hepatitis severity in US and Japanese patients. Dig Dis Sci 2016; 61(12) 3506-3512

[30] Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): a multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther 2022; 233: 108024

[31] Bucala R. MIF, MIF alleles, and prospects for therapeutic intervention in autoimmunity. J Clin Immunol 2013; 33(Suppl 1, Suppl 1): S72-S78

[32] <Macrophage Migration Inhibitory Factor Gene Polymorphism.pdf > .

[33] Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: a potential tumor therapeutic target. Int J Cancer 2023; 152(07) 1290-1303

[34] Khan KD, Emmanouilides C, Benson Jr DM.et al. A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma. Clin Cancer Res 2006; 12(23) 7046-7053

[35] Nakase K, Kita K, Katayama N. IL-2/IL-3 interplay mediates growth of CD25 positive acute myeloid leukemia cells. Med Hypotheses 2018; 115: 5-7

[36] Gout DY, Groen LS, van Egmond M. The present and future of immunocytokines for cancer treatment. Cell Mol Life Sci 2022; 79(10) 509

[37] Zeng Z, Lan T, Wei Y, Wei X. CCL5/CCR5 axis in human diseases and related treatments. Genes Dis 2022; 9(01) 12-27

[38] Aldinucci D, Borghese C, Casagrande N. The CCL5/CCR5 axis in cancer progression. Cancers (Basel) 2020; 12(07) 1765

[39] Mukaida N, Tanabe Y, Baba T. Chemokines as a conductor of bone marrow microenvironment in chronic myeloid leukemia. Int J Mol Sci 2017; 18(08) 1824

[40] Casagrande N, Borghese C, Visser L, Mongiat M, Colombatti A, Aldinucci D. CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth. Haematologica 2019; 104(03) 564-575

[41] Popek-Marciniec S, Styk W, Wojcierowska-Litwin M.et al. The relationship of CCL5 and CCR1 variants with response rate and survival taking into account thalidomide/bortezomib treatment in patients with multiple myeloma. J Clin Med 2023; 12(06) 2384

[42] Tang CH, Yamamoto A, Lin YT, Fong YC, Tan TW. Involvement of matrix metalloproteinase-3 in CCL5/CCR5 pathway of chondrosarcomas metastasis. Biochem Pharmacol 2010; 79(02) 209-217

[43] Schlecker E, Stojanovic A, Eisen C.et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol 2012; 189(12) 5602-5611

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