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Open Access 01-04-2022 | Multiple Sclerosis | Original Article

Multiple sclerosis and genetic polymorphisms in fibrinogen-mediated hemostatic pathways: a case–control study

Authors: Gianmarco Abbadessa, Giuseppina Miele, Andrea Di Pietro, Maddalena Sparaco, Raffaele Palladino, Ignazio Armetta, Giovanna D’Elia, Francesca Trojsi, Elisabetta Signoriello, Giacomo Lus, Luigi Lavorgna, Simona Bonavita

Published in: Neurological Sciences | Issue 4/2022

Abstract

Introduction

Blood coagulation constituents might exert immunomodulatory functions in the CNS and may trigger neuroinflammation and demyelination. We evaluated whether particular single-nucleotide polymorphisms (SNPs), thought to be involved in fibrinogen-mediated hemostatic pathways, are overrepresented in patients with MS compared with controls.

Methods

The case–control study consisted of 119 MS patients recruited consecutively at our clinic, and 68 healthy controls. Afterwards, we created a cumulative genetic risk score (CGRS) which included the 5 selected hemostatic risk alleles (Beta-Fibrinogen 455G/A, Glycoprotein IIIa P1A2, Factor V Leiden, Factor V H2R, and Prothrombin 20210G/A). Multivariate ordinal logistic regression and multivariate multinomial logistic regression were applied to evaluate the effect of CGRS on MS susceptibility.

Results

The FGB 455 G/A and Factor V H1299R variants might be associated with MS status, in the recessive and dominant model, respectively. A cumulative association of the five SNPs investigated with the disease was observed.

Discussion

We found that MS patients carried more pro-hemostatic variants than healthy controls. An increasing number of unfavorable alleles might increase the likelihood of being in the MS group, in the cumulative analysis. Our findings encourage to evaluating these variants in a larger population-based cohort.

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Reich DS, Lucchinetti CF, Calabresi PA (2018) Multiple sclerosis. N Engl J Med 378(2):169–180. https://doi.org/10.1056/NEJMra1401483CrossRefPubMedPubMedCentral

D’Haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J (2011) Vascular aspects of multiple sclerosis. Lancet Neurol 10:657–666. https://doi.org/10.1016/S1474-4422(11)70105-3CrossRefPubMed

Merker M, Eichler S, Herrmann AM, Wiendl H, Kleinschnitz C, Göbel K, Meuth SG (2017) Rivaroxaban ameliorates disease course in an animal model of multiple sclerosis. J Neuroimmunol 15(313):125–128. https://doi.org/10.1016/j.jneuroim.2017.08.013CrossRef

Plantone D, Inglese M, Salvetti M, Koudriavtseva T (2019) A perspective of coagulation dysfunction in multiple sclerosis and in experimental allergic encephalomyelitis [published correction appears in Front Neurol 2019 Mar 12;10:210]. Front Neurol 9:1175. https://doi.org/10.3389/fneur.2018.01175CrossRefPubMedPubMedCentral

Lee NJ, Ha SK, Sati P et al (2018) Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination. Brain 141:1637–1649. https://doi.org/10.1093/brain/awy082CrossRefPubMedPubMedCentral

Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA, Deerinck TJ, Smirnoff DS, Bedard C, Hakozaki H, Gonias Murray S, Ling JB, Lassmann H, Degen JL, Ellisman MH, Akassoglou K (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227. https://doi.org/10.1038/ncomms2230CrossRefPubMed

Ryu JK, Petersen MA, Murray SG et al (2015) Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 6:8164. https://doi.org/10.1038/ncomms9164CrossRefPubMed

Ryu JK, Rafalski VA, Meyer-Franke A et al (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212–1223CrossRef

Zhao F, Song M, Wang Y, Wang W (2016) Genetic model. J Cell Mol Med 20(4):765. https://doi.org/10.1111/jcmm.12751CrossRefPubMedPubMedCentral

10.

Liyanarachchi S, Wojcicka A, Li W et al (2013) Cumulative risk impact of five genetic variants associated with papillary thyroid carcinoma. Thyroid 23(12):1532–1540. https://doi.org/10.1089/thy.2013.0102CrossRefPubMedPubMedCentral

11.

Rothman KJ (1990) No adjustments are needed for multiple comparisons. Epidemiology 1(1):43–46CrossRef

12.

Alexander TA, Machiela MJ (2020) LDpop: an interactive online tool to calculate and visualize geographic LD patterns. BMC Bioinformatics 21(1):14. https://doi.org/10.1186/s12859-020-3340-1

13.

Cernera G, Comegna M, Gelzo M et al (2021) Molecular analysis of prothrombotic gene variants in patients with acute ischemic stroke and with transient ischemic attack. Medicina 57(7):723CrossRef

14.

Kucharska-Newton AM, Monda KL, Campbell S et al (2011) Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 216(1):151–156. https://doi.org/10.1016/j.atherosclerosis.2011.01.038CrossRefPubMedPubMedCentral

15.

Di Castelnuovo A, de Gaetano G, Donati MB, Iacoviello L (2001) Platelet glycoprotein receptor IIIa polymorphism PLA1/PLA2 and coronary risk: a meta-analysis. Thromb Haemost 85(4):626–633CrossRef

16.

Todinova S, Komsa-Penkova R, Krumova S, Taneva SG, Golemanov G, Georgieva G, Tonchev P, Tsankov B, Beshev L, Balashev K, Andreeva TD (2017) PlA2 Polymorphism in glycoprotein IIb/IIIa modulates the morphology and nanomechanics of platelets. Clin Appl Thromb Hemost 23(8):951–960. https://doi.org/10.1177/1076029616687847CrossRefPubMed

17.

Saluk-Bijak J, Dziedzic A, Bijak M (2019) Pro-thrombotic activity of blood platelets in multiple sclerosis. Cells 1;8(2):110. https://doi.org/10.3390/cells8020110

18.

Marcos-Ramiro B, Oliva Nacarino P, Serrano-Pertierra E et al (2014) Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neurosci 15:110. https://doi.org/10.1186/1471-2202-15-110CrossRefPubMedPubMedCentral

19.

Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A (2008) Evidence of platelet activation in multiple sclerosis. J Neuroinflammation 5:27. https://doi.org/10.1186/1742-2094-5-27CrossRefPubMedPubMedCentral

20.

Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508. https://doi.org/10.1038/nm0502-500CrossRefPubMed

21.

Morel A, Bijak M, Miller E, Rywaniak J, Miller S, Saluk J (2015) Relationship between the increased haemostatic properties of blood platelets and oxidative stress level in multiple sclerosis patients with the secondary progressive stage. Oxid Med Cell Longev 2015:240918. https://doi.org/10.1155/2015/240918CrossRefPubMedPubMedCentral

22.

Morel A, Rywaniak J, Bijak M, Miller E, Niwald M, Saluk J (2017) Flow cytometric analysis reveals the high levels of platelet activation parameters in circulation of multiple sclerosis patients. Mol Cell Biochem 430:69–80. https://doi.org/10.1007/s11010-017-2955-7CrossRefPubMedPubMedCentral

23.

Tiedje V, Dunkler D, Ay C, Horvath B et al (2011) The role of fibrinogen plasma levels, the -455G>A fibrinogen and the factor XIII A subunit (FXIII-A) Val34Leu polymorphism in cancer-associated venous thrombosis. Thromb Haemost 106(5):908–913. https://doi.org/10.1160/TH11-04-0278CrossRefPubMed

24.

Demirci FY, Dressen AS, Kammerer CM, Barmada MM, Kao AH, Ramsey-Goldman R, Manzi S, Kamboh MI (2011) Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus. J Rheumatol 38(4):652–657. https://doi.org/10.3899/jrheum.100728CrossRefPubMedPubMedCentral

25.

Gobel K, Kraft P, Pankratz S et al (2016) Prothrombin and factor X are elevated in multiple sclerosis patients. Ann Neurol 80:946–951. https://doi.org/10.1002/ana.24807CrossRefPubMed

26.

Parsons ME, O’Connell K, Allen S et al (2017) Thrombin generation correlates with disease duration in multiple sclerosis (MS): novel insights into the MS-associated prothrombotic state. Mult Scler J Exp Transl Clin 3:2055217317747624. https://doi.org/10.1177/2055217317747624CrossRefPubMedPubMedCentral

27.

Magliozzi R, Hametner S, Facchiano F et al (2019) Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis. Ann Clin Transl Neurol 6:2150–2163. https://doi.org/10.1002/acn3.50893CrossRefPubMedPubMedCentral

28.

Han MH, Hwang SI, Roy DB et al (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451:1076–1081. https://doi.org/10.1038/nature06559CrossRefPubMed

29.

Vos CM, Geurts JJ, Montagne L et al (2005) Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol Dis 20:953–960. https://doi.org/10.1016/j.nbd.2005.06.012CrossRefPubMed

30.

Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815. https://doi.org/10.1093/brain/awm236CrossRefPubMed

31.

Petersen MA, Ryu JK, Akassoglou K (2018) Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat Rev Neurosci 19:283–301. https://doi.org/10.1038/nrn.2018.13CrossRefPubMedPubMedCentral

32.

International Multiple Sclerosis Genetics Consortium (2019) Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365(6460):eaav7188

Title: Multiple sclerosis and genetic polymorphisms in fibrinogen-mediated hemostatic pathways: a case–control study
Authors: Gianmarco Abbadessa
Giuseppina Miele
Andrea Di Pietro
Maddalena Sparaco
Raffaele Palladino
Ignazio Armetta
Giovanna D’Elia
Francesca Trojsi
Elisabetta Signoriello
Giacomo Lus
Luigi Lavorgna
Simona Bonavita
Publication date: 01-04-2022
Publisher: Springer International Publishing
Keyword: Multiple Sclerosis
Published in: Neurological Sciences / Issue 4/2022
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-021-05608-1

At a glance: The STEP trials

Springer Medicine

Multiple sclerosis and genetic polymorphisms in fibrinogen-mediated hemostatic pathways: a case–control study

Abstract

Introduction

Methods

Results

Discussion

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Discussion

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