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Current Neurovascular Research

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ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

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Research Article

Association of Variants in FCGR2A, PTPN2, and GM-CSF with Cerebral Cavernous Malformation: Potential Biomarkers for a Symptomatic Disease

Author(s): Gustavo da Fontoura Galváo, Fabrícia Lima Fontes-Dantas, Elielson Veloso da Silva , Soniza Vieira Alves-Leon and Jorge Marcondes de Souza*

Volume 18, Issue 2, 2021

Published on: 03 June, 2021

Page: [172 - 180] Pages: 9

DOI: 10.2174/1567202618666210603125630

Price: $65

Abstract

Background: Cerebral Cavernous Malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of people affected will develop clinical symptoms and the molecular mechanisms underlying lesional activity remain unclear. We analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients. We looked for plasmatic inflammatory cytokines, checking for a pattern of plasma expression heterogeneity and any correlation with genetic variations identified with different CCM clinical phenotypes.

Methods: This was a case-control study from a long-term follow-up cohort including 23 CCM patients, of which 16 were symptomatic, and 7 were asymptomatic. A 200-SNP panel was considered through next-generation sequencing and 18 different plasma molecules were assessed through a suspension array system.

Results: Fcγ receptor IIa rs1801274 (FCGR2A) and protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were statistically different between groups. Patients who had a combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in life. The combination of genetic polymorphisms and serum level of GM-CSF showed the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)].

Conclusion: We have shown that SNPs in inflammation genes might be related to a symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) is possibly capable of predicting a symptomatic phenotype during a patient’s lifetime.

Keywords: PTPN2, GM-CSF, cerebral cavernous malformation, biomarkers, Fcγ receptor IIa, peripheral plasma.

« Previous Next »
[1]
Flemming Kelly D. Population-based prevalence of cerebral cavernous malformations in older adults: Mayo clinic study of aging. JAMA Neurol 2017; 74(7): 801-5.
[2]
Spiegler S, Rath M, Paperlein C, Felbor U. Cerebral cavernous malformations: An update on prevalence, molecular genetic analyses, and genetic counselling. Mol Syndromol 2018; 9(2): 60-9.
[http://dx.doi.org/10.1159/000486292] [PMID: 29593473]
[3]
Dashti SR, Hoffer A, Yin C. Hu, Warren R. Selman. Molecular genetics of familial cerebral cavernous malformations. Neurosurgical focus 2006; 21(1): e2.
[PMID: 16859255]
[4]
Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol 2007; 6(3): 237-44.
[http://dx.doi.org/10.1016/S1474-4422(07)70053-4] [PMID: 17303530]
[5]
Gault J, Sain S, Hu LJ, Awad IA. Spectrum of genotype and clinical manifestations in cerebral cavernous malformations. Neurosurgery 2006; 59(6): 1278-84.
[http://dx.doi.org/10.1227/01.NEU.0000249188.38409.03] [PMID: 17277691]
[6]
Gross BA, Lin N, Du R, Day AL. The natural history of intracranial cavernous malformations. J Neurosurg 2011; 114(5): 1250-6.
[http://dx.doi.org/10.3171/2010.12.JNS101623] [PMID: 21250802]
[7]
Al-Shahi Salman R, Hall JM, Horne MA, et al. Untreated clinical course of cerebral cavernous malformations: A prospective, population-based cohort study. Lancet Neurol 2012; 11(3): 217-24.
[8]
de Souza JM, Domingues RC, Cruz LCH Jr, Domingues FS, Iasbeck T, Gasparetto EL. Susceptibility-weighted imaging for the evaluation of patients with familial cerebral cavernous malformations: A comparison with t2-weighted fast spin-echo and gradient-echo sequences. AJNR Am J Neuroradiol 2008; 29(1): 154-8.
[http://dx.doi.org/10.3174/ajnr.A0748] [PMID: 17947370]
[9]
Barker FG II, Amin-Hanjani S, Butler WE, et al. Temporal clustering of hemorrhages from untreated cavernous malformations of the central nervous system. Neurosurgery 2001; 49(1): 15-24.
[PMID: 11440436]
[10]
Al-Holou WN, O’Lynnger TM, Pandey AS, et al. Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr 2012; 9(2): 198-205.
[http://dx.doi.org/10.3171/2011.11.PEDS11390] [PMID: 22295927]
[11]
Girard R, Fam MD, Zeineddine HA, et al. Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations. J Neurosurg 2017; 127(1): 102-10.
[http://dx.doi.org/10.3171/2016.5.JNS16687] [PMID: 27494817]
[12]
Mikati AG, Tan H, Shenkar R, et al. Dynamic permeability and quantitative susceptibility: Related imaging biomarkers in cerebral cavernous malformations. Stroke 2014; 45(2): 598-601.
[http://dx.doi.org/10.1161/STROKEAHA.113.003548] [PMID: 24302484]
[13]
Plummer NW, Gallione CJ, Srinivasan S, Zawistowski JS, Louis DN, Marchuk DA. Loss of p53 sensitizes mice with a mutation in Ccm1 (KRIT1) to development of cerebral vascular malformations. Am J Pathol 2004; 165(5): 1509-18.
[http://dx.doi.org/10.1016/S0002-9440(10)63409-8] [PMID: 15509522]
[14]
Shi C, Shenkar R, Du H, et al. Immune response in human cerebral cavernous malformations. Stroke 2009; 40(5): 1659-65.
[http://dx.doi.org/10.1161/STROKEAHA.108.538769] [PMID: 19286587]
[15]
Shi C, Shenkar R, Kinloch A, et al. Immune complex formation and in situ B-cell clonal expansion in human cerebral cavernous malformations. J Neuroimmunol 2014; 272(1-2): 67-75.
[http://dx.doi.org/10.1016/j.jneuroim.2014.04.016] [PMID: 24864012]
[16]
Choquet H, Pawlikowska L, Nelson J, et al. Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc Dis 2014; 38(6): 433-40.
[http://dx.doi.org/10.1159/000369200] [PMID: 25472749]
[17]
Girard R, Zeineddine HA, Fam MD, et al. Plasma biomarkers of inflammation reflect seizures and hemorrhagic activity of cerebral cavernous malformations. Transl Stroke Res 2018; 9(1): 34-43.
[http://dx.doi.org/10.1007/s12975-017-0561-3] [PMID: 28819935]
[18]
Girard R, Zeineddine HA, Koskimäki J, et al. Plasma biomarkers of inflammation and angiogenesis predict cerebral cavernous malformation symptomatic hemorrhage or lesional growth. Circ Res 2018; 122(12): 1716-21.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.312680] [PMID: 29720384]
[19]
Girard R, Khanna O, Shenkar R, et al. Peripheral plasma vitamin D and non-HDL cholesterol reflect the severity of cerebral cavernous malformation disease. Biomarkers Med 2016; 10(3): 255-64.
[http://dx.doi.org/10.2217/bmm.15.118] [PMID: 26861901]
[20]
Polster SP, Sharma A, Tanes C, et al. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma. Nat Commun 2020; 11(1): 2659.
[http://dx.doi.org/10.1038/s41467-020-16436-w] [PMID: 32461638]
[21]
Lyne SB, Girard R, Koskimäki J, et al. Biomarkers of cavernous angioma with symptomatic hemorrhage. JCI Insight 2019; 4(12): e128577.
[http://dx.doi.org/10.1172/jci.insight.128577] [PMID: 31217347]
[22]
Akers A, Al-Shahi Salman R, Awad IA, et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: Consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery 2017; 80(5): 665-80.
[http://dx.doi.org/10.1093/neuros/nyx091] [PMID: 28387823]
[23]
Polster SP, Stadnik A, Akers AL, et al. Atorvastatin treatment of cavernous angiomas with symptomatic hemorrhage exploratory proof of concept (at cash epoc) trial. Neurosurgery 2019; 85(6): 843-53.
[http://dx.doi.org/10.1093/neuros/nyy539] [PMID: 30476251]
[24]
Fontes FL, de Araújo LF, Coutinho LG, Leib SL, Agnez-Lima LF. Genetic polymorphisms associated with the inflammatory response in bacterial meningitis. BMC Med Genet 2015; 16: 70.
[http://dx.doi.org/10.1186/s12881-015-0218-6] [PMID: 26316174]
[25]
Youden WJ. Index for rating diagnostic tests. Cancer 1950; 3(1): 32-5.
[http://dx.doi.org/10.1002/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3] [PMID: 15405679]
[26]
Lovric M. International encyclopedia of statistical science. Berlin, Germany: Springer 2010.
[27]
Shenkar R, Shi C, Check IJ, Lipton HL, Awad IA. Concepts and hypotheses: Inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations. Neurosurgery 2007; 61(4): 693-702.
[http://dx.doi.org/10.1227/01.NEU.0000298897.38979.07] [PMID: 17986930]
[28]
Fontes-Dantas FL, Galvão G, Veloso E, et al. Novel CCM1 (KRIT1) mutation detection in Brazilian familial Cerebral cavernous malformation: Different genetic variants in inflammation, oxidative stress and drug metabolism genes affect disease aggressiveness. World Neurosurg 2020; S1878-8750(20): 30394-6.
[29]
Topham NJ, Hewitt EW. Natural killer cell cytotoxicity: How do they pull the trigger? Immunology 2009; 128(1): 7-15.
[http://dx.doi.org/10.1111/j.1365-2567.2009.03123.x] [PMID: 19689731]
[30]
Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 2000; 6(4): 443-6.
[http://dx.doi.org/10.1038/74704] [PMID: 10742152]
[31]
Li X, Gibson AW, Kimberly RP. Human FcR polymorphism and disease. Curr Top Microbiol Immunol 2014; 382: 275-302.
[http://dx.doi.org/10.1007/978-3-319-07911-0_13] [PMID: 25116105]
[32]
Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol 2013; 6: 1.
[http://dx.doi.org/10.1186/1756-8722-6-1] [PMID: 23286345]
[33]
Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47(9): 979-86.
[http://dx.doi.org/10.1038/ng.3359] [PMID: 26192919]
[34]
Khor CC, Davila S, Breunis WB, et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet 2011; 43(12): 1241-6.
[http://dx.doi.org/10.1038/ng.981] [PMID: 22081228]
[35]
Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 2015; 47(12): 1457-64.
[http://dx.doi.org/10.1038/ng.3434] [PMID: 26502338]
[36]
Song GG, Lee YH. Associations between FCGR2A rs1801274, FCGR3A rs396991, FCGR3B NA1/NA2 polymorphisms and periodontitis: A meta-analysis. Mol Biol Rep 2013; 40(8): 4985-93.
[http://dx.doi.org/10.1007/s11033-013-2599-y] [PMID: 23649770]
[37]
Zhang C, Wang W, Zhang H, Wei L, Guo S. Association of FCGR2A rs1801274 polymorphism with susceptibility to autoimmune diseases: A meta-analysis. Oncotarget 2016; 7(26): 39436-43.
[http://dx.doi.org/10.18632/oncotarget.9831] [PMID: 27270653]
[38]
Zhang D, Kinloch AJ, Srinath A, et al. Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu. J Autoimmun 2020; 113: 102469.
[http://dx.doi.org/10.1016/j.jaut.2020.102469] [PMID: 32362501]
[39]
Hussain K, Hargreaves CE, Rowley TF, et al. Impact of human fcγr gene polymorphisms on igg-triggered cytokine release: Critical importance of cell assay format. Front Immunol 2019; 10: 390.
[http://dx.doi.org/10.3389/fimmu.2019.00390] [PMID: 30899264]
[40]
Yesmin K, Hargreaves C, Newby PR, et al. Association of FcGRIIa with Graves’ disease: A potential role for dysregulated autoantibody clearance in disease onset/progression. Clin Endocrinol (Oxf) 2010; 73(1): 119-25.
[http://dx.doi.org/10.1111/j.1365-2265.2010.03780.x] [PMID: 20148910]
[41]
Kwon YC, Kim JJ, Yun SW, et al. Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease. PLoS One 2017; 12(9): e0184248.
[http://dx.doi.org/10.1371/journal.pone.0184248] [PMID: 28886140]
[42]
Awad IA, Polster SP. Cavernous angiomas: Deconstructing a neurosurgical disease. J Neurosurg 2019; 131(1): 1-13.
[http://dx.doi.org/10.3171/2019.3.JNS181724] [PMID: 31261134]
[43]
Xu Y, Hunt NH, Bao S. The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation. Cell Res 2008; 18(12): 1220-9.
[http://dx.doi.org/10.1038/cr.2008.310] [PMID: 19030026]
[44]
Curnow SJ, Scheel-Toellner D, Jenkinson W, et al. Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling. J Immunol 2004; 173(8): 5290-7.
[http://dx.doi.org/10.4049/jimmunol.173.8.5290] [PMID: 15470075]
[45]
Long SA, Cerosaletti K, Wan JY, et al. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells. Genes Immun 2011; 12(2): 116-25.
[http://dx.doi.org/10.1038/gene.2010.54] [PMID: 21179116]
[46]
Svensson MN, Doody KM, Schmiedel BJ, et al. Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. J Clin Invest 2019; 129(3): 1193-210.
[http://dx.doi.org/10.1172/JCI123267] [PMID: 30620725]
[47]
Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic variations of ptpn2 and ptpn22: Role in the pathogenesis of type 1 diabetes and crohn’s disease. Front Cell Infect Microbiol 2015; 5: 95.
[http://dx.doi.org/10.3389/fcimb.2015.00095] [PMID: 26734582]
[48]
Spalinger MR, Manzini R, Hering L, et al. PTPN2 regulates inflammasome activation and controls onset of intestinal inflammation and colon cancer. Cell Rep 2018; 22(7): 1835-48.
[http://dx.doi.org/10.1016/j.celrep.2018.01.052] [PMID: 29444435]
[49]
Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8(7): 533-44.
[http://dx.doi.org/10.1038/nri2356] [PMID: 18551128]
[50]
Hamilton JA, Achuthan A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol 2013; 34(2): 81-9.
[http://dx.doi.org/10.1016/j.it.2012.08.006] [PMID: 23000011]
[51]
Schäbitz WR, Krüger C, Pitzer C, et al. A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab 2008; 28(1): 29-43.
[http://dx.doi.org/10.1038/sj.jcbfm.9600496] [PMID: 17457367]
[52]
Kiyota T, Machhi J, Lu Y, et al. Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer’s disease mice. J Neuroimmunol 2018; 319: 80-92.
[http://dx.doi.org/10.1016/j.jneuroim.2018.03.009] [PMID: 29573847]
[53]
Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009; 33(1): 3-11.
[http://dx.doi.org/10.1016/j.jaut.2009.03.007] [PMID: 19349147]
[54]
Albert FW, Kruglyak L. The role of regulatory variation in complex traits and disease. Nat Rev Genet 2015; 16(4): 197-212.
[http://dx.doi.org/10.1038/nrg3891] [PMID: 25707927]

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