Neurovascular Genetics is an important part of the research in our Laboratory.

Firstly, we are participating in the first pharmacogenomic study in patients treated with t-PA, the Geno-tPA project. In this project, we work on polymorphisms in genes related to biological processes such as inflammation, proteolysis and hemostasis, which are capable of modifying the response to thrombolysis treatment. The goal is to analyze about 200 polymorphisms in 540 patients. More than 13 mutations have been studied already and some articles have been published, showing for example for the first time the risk of suffering hemorrhagic complications and the recanalization rates after treatment are determined genetically through genes such as the factor XIII (PMID: 16857944), the Angiotensin Converting Enzyme (PMID: 16442232) and the Thrombin-activatable fibrinolysis inhibitor (PMID: 17723126).

Secondly, the GRECOS project (Genotyping RECurrence Of Stroke) is a genetic ongoing multi-center prospective longitudinal cohort study which primary’s objective is to identify of the genetic markers that determine the risk to suffer a stroke recurrence. The recruiting process started in February 2007, and the final cohort should be composed of about 4050 patients who suffered a first episode of ischemic or hemorrhagic stroke. In this group of patients, we will analyze about 200 polymorphisms in candidate genes related to inflammation, hemostasis, apoptosis, angiogenesis, proteolisis and other processes. The genotyping will be performed through the SNPlex platform from the National Centre of Genotyping ( http://www.cegen.org ).The last data on the recruiting process are accessible here (powerpoint) .

Thirdly, the CONIC project is a case-control study which pretends to determine the genetic risk factors associated to stroke. Two different group of persons will be recruited and various biological samples will be extracted, such as DNA, RNA, plasma and serum, as well as routine information. The first group of persons, the “cases” will be composed by patients from the Geno-tPA study and are patients who suffered an ischemic stroke. The second group, the “controls” will be formed by 540 persons healthy of vascular diseases. 200 polymorphisms will be analyzed and differences between the groups of cases and controls will be studied. This will lead to the identification of genes and genetic variants (polymorphisms but also haplotypes or copy number variants) implicated in the stroke disease. Moreover, functional studies will be performed to determine the exact contribution of each variant described at the biological level.

A part from these studies, our group offers a service of Neurovascular Genetic Consult by a neurologist. This consult aims to diagnose specifically patients (and their families) with cerebrovascular diseases of genetic origin. A special attention will be dedicated to diseases such as Fabry’s disease, CADASIL, Rendu-Osler, but we also regularly attend patients with any suspicion of genetic and hereditary cerebrovascular disease. From this consult, we recently started a multicentric study to determine the prevalence of the Fabry’s disease in young stroke patients in Spain and the results will be available in 2008. To obtain more information on the Neurovascular Genetic Consult, you can send us an email though the “contact” section of this website.

Services offered by our genetic department:

We offer consult by a specialized neurologist and genetic diagnostic of CADASIL:

Exons 3 y 4: 365 Euros Time necessary: about 3 weeks

Complete gene: 1.177 Euros Time necessary: about 2 months

(Prices obtained from the Diario Oficial de Galicia Nº141 21 julio 2006, Anexo V)

The Neurovascular Research Laboratory actively collaborates in two consorcia: The IGSC (International Genetic Stroke Consortium), a consortium that joint the most remarkable international groups working in the genetic component of stroke. The other one is the GeneStroke consortium, a national consortium in which we are the coordinators. The aim of this consortium is the collaboration among different centers and to perform genome-Wide Analysis in spanish population.

Bibliography:

1.Palenzuela L, Vives Bauza C, Fernandez-Cadenas I, Meseguer A, Font N, Sarret E, Schwartz S, Andreu AL. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene.
J Med Genet . 2002 Oct; 39(10): E67.

2.Palenzuela L, Andreu AL, Gamez J, Vila MR, Kunimatsu T, Meseguer A, Cervera C, Fernández-Cadenas I, Van der Ven PF, Nygaard TG, Bonilla E, Hirano M. A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2.
Neurology . 2003 Aug 12; 61(3): 404-6.

3.Gamez J, Rubio JC, Martín MA, Fernandez-Cadenas I, Garcia-Arumi E, Andreu AL, Arenas J. Two novel mutations in the muscle glycogen phosphorylase gene in McArdle's disease .
Muscle Nerve . 2003 Sep; 28(3): 380-2.

4.Montaner J, Fernandez-Cadenas I, Molina CA, Monasterio J, Arenillas JF, Ribo M, Quintana M, Chacon P, Andreu AL, Alvarez-Sabin J. Safety profile of tissue plasminogen activator treatment among stroke patients carrying a common polymorphism (C-1562T) in the promoter region of the matrix metalloproteinase-9 gene.
Stroke . 2003 Dec; 34(12): 2851-5. Epub 2003 Nov 06.

5.Fernandez-Cadenas I, Andreu AL, Gamez J, Gonzalo R, Martin MA, Rubio JC, Arenas J. Splicing mosaic of the myophosphorylase gene due to a silent mutation in McArdle disease.
Neurology. 2003 Nov 25; 61(10): 1432-4.

6-Paradas C, Fernandez-Cadenas I, Gallardo E, Llige D, Arenas J, Illa I, Andreu AL. Variable presentation of the clinical phenotype of McArdle's disease in a kindred harbouring a novel compound genotype in the muscle glycogen phosphorylase gene.
Neurosci Lett. 2005 Sep 8

7- Fernández-Cadenas I, Molina CA, Alvarez-Sabín J, Ribó M, Penalba A, Ortega Torres L, Delgado P, Quintana M, Rosell A, Montaner J. ACE gene polymorphisms influence t-PA-induced brain vessel reopening following ischemic stroke. Neuroscience Letters 2006;398: 167-171

8-Fernández-Cadenas I, Alvarez-Sabín J, Molina CA, Ribó M, Penalba A, Ortega-Torres L, Delgado P, Rosell A, Montaner J. Influencia del genotipo del ApoE sobre la eficacia y seguridad del tratamiento trombolítico en el ictus isquémico.Neurologia 2006;21(4):176-180.

9-González-Conejero R, Fernández-Cadenas I, Iniesta JA, Marti-Fabregas J, Obach V,Alvarez-Sabín J, Vicente V, Corral J, Montaner J. Role of fibrinogen levels and factor XIII V34L polymorphism in thrombolytic therapy in stroke patients. Stroke 2006;37(9):2288-2293.

10-Joan Montaner, Israel Fernandez-Cadenas, Carlos A Molina, Marc Ribo, Rafael Huertas, Anna Rosell, Anna Penalba, Laura Ortega, Pilar Chacon, and Jose Alvarez-Sabin. Post-stroke C-reactive protein is a powerful prognostic tool among candidates for thrombolysis. 2006. Stroke 2006; 37(5):1205-10.

11- Mendioroz M, Fernandez-Cadenas I, Montaner J. [Neurological manifestations of Fabry disease] .Rev Neurol . 2006; 43:739-745. Spanish.

12- Rubio JC, Lucia A, Fernandez-Cadenas I, Cabello A, Blazquez A, Gamez J, Andreu AL, Martin MA, Arenas J. Novel mutation in the PYGM gene resulting in McArdle disease . Arch Neurol. 2006; 63:1782-1784.

13- I. Fernández-Cadenas, G. Nogales-Gadea, D. Llige, J.C. Rubio, J. Montaner, J. Arenas, M. Raspall-Chaure, M. Roig-Quilis, AL. Andreu.Mutaciones privadas en el gen de la miofosforilasa: primer caso en un español de origen latinoamericano [spanish] . Rev Neurología. 2009. 45(5):280-3.

14- Gisela Nogales-Gadea, Juan Carlos Rubio, Israel Fernandez-Cadenas, Ines Garcia-Consuegra, Alejandro Lucia, Ana Cabello, Elena Garcia-Arumi, Joaquin Arenas, Antoni L. Andreu, Miguel A. Martín. Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay. Human Mutation 2008;29(2):277-83.

15- I. Fernandez-Cadenas, J . Alvarez-Sabin, M. Ribo, M. Rubiera, M. Mendioroz, C. A. molina, A. Rosell, J . Montaner. Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients. J of Thrombosis and Haemostasis. 2007 Sep;5(9):1862-8

16- Arenillas JF, Alvarez-Sabín J, Molina CA, Chacón P, Fernández-Cadenas I, Ribó M, Delgado P, Rubiera M, Penalba A, Rovira A, Montaner J Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis. Stroke . 2008 May; 39 ( 5 ): 1456-63

17- Domingues-Montanari S, Mendioroz M, del Rio-Espinola A, Fernández-Cadenas I, Montaner J. Genetics of stroke: a review of recent advances. Expert Rev Mol Diagn. 2008 Jul; 8 ( 4 ): 495-513 .

18- del Río-Espínola A, Mendióroz M, Domingues-Montanari S, Pozo-Rosich P, Solé E, Fernández-Morales J, Fernández-Cadenas I, Montaner J. CADASIL management or what to do when there is little one can do. Expert Rev Neurother . 2009 Feb;9(2):197-210.

19-Arenillas JF, Massot A, Alvarez-Sabín J, Fernandez-Cadenas I, Del Rio-Espinola A, Chacon P, Quintana M, Molina CA, Rovira A, Montaner J. C-Reactive Protein Gene C1444T Polymorphism and Risk of Recurrent Ischemic Events in Patients with Symptomatic Intracranial Atherostenoses. Cerebrovasc Dis . 2009 Jun 3;28(1):95-102

20- Mendioroz M, Fernández-Cadenas I, Alvarez-Sabín J, Rosell A, Quiroga D, Cuadrado E, Delgado P, Rubiera M, Ribó M, Molina C, Montaner J. Endogenous activated protein C predicts hemorrhagic transformation and mortality after tissue plasminogen activator treatment in stroke patients. Cerebrovasc Dis . 2009;28(2):143-50

21-Domingues-Montanari S, Fernández-Cadenas I, Del Río-Espinola A, Mendioroz M, Fernandez-Morales J, Corbeto N, Delgado P, Ribó M, Rubiera M, Obach V, Martí-Fàbregas J, Freijo M, Serena J, Montaner J. KCNK17 genetic variants in ischemic stroke. Atherosclerosis . 2009 Jul 30.

22- I. Fernandez-Cadenas, PhD; M. Mendioroz, MD; J. Munuera, MD; J. Alvarez-Sabin, MD, PhD; A. Rovira, MD, PhD; A. Quiroga, N. Corbeto, MsC; M. Rubiera, MD, PhD; P. Delgado, MD, PhD; A. Rosell, PhD; M. Ribó, MD, PhD; CA. Molina, MD, PhD; J. Montaner, MD, PhD. Lower concentrations of thrombin-antithrombin complex (TAT) correlate to higher recanalization rates among ischemic stroke patients treated with t-PA. Thrombosis and Haemostasis . 2009

23-I. Fernandez-Cadenas, PhD; A. Del Rio-Espinola, MsC; M. Rubiera, MD, PhD; M. Mendioroz, MD; S. Domingues-Montanari, MsC; N; E. Cuadrado, MsC; M. Hernandez-Guillamon, PhD; A. Rosell, PhD; M. Ribo, MD, PhD; J. Alvarez-Sabin, MD, PhD; CA. Molina, MD, PhD; J. Montaner, MD, PhD . PAI-1 4G5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients. International journal of neuroscience . 2010 (in press).

24-Domingues-Montanari S, Fernández-Cadenas I, Del Río-Espinola A, Corbeto N, Krug T, Manso H, Gouveia L, Sobral J, Mendioroz M, Fernández-Morales J, Alvarez-Sabin J, Ribó M, Rubiera M, Obach V, Martí-Fàbregas J, Freijo M, Serena J, Ferro JM, Vicente AM, Oliveira SA, Montaner J. Association of a genetic variant in the ALOX5AP gene with higher risk of ischemic stroke. A case-control, meta-analysis and functional study. Cerebrovasc Dis . 2010 (in press)

25- Domingues-Montanari S, Fernández-Cadenas I, Del Río-Espinola A, Mendioroz M, Ribo M, Obach V, Marti-Fabregas J, Freijo M, Serena V, Corbeto N, Chacon P, Alvarez-Sabin J, Montaner J. The I/D polymorphism of the ACE1 is not associated with ischemic stroke in Spanish individuals . Eur J Neurol . 2010. (in press)

26- Del Río Espínola A, Solé E, Montaner J. Pathophysiology of CADASIL disease . Med Clin (Barc). 2009 Dec 24.

Genetics team:

Israel Fernández-Cadenas

Biologist, PhD.

Genetic area responsible

Maite Mendioroz

Neurologist, MD.

Genetics Consult and GRECOS Project.

Sophie Domingues-Montanari

Degree in Biochemistry, MsC.

CONIC Project

Alberto Del Rio-Espinola

Degree in Biotechnology and Biochemistry, MsC.

Geno-tPA Project

Cristina Nafria

Psychologist, MsC.

GRECAS Project

Laura Deu

Nurse

GRECOS Project