VEGF Haplotypes are Associated with Increased Risk to Progressive Supranuclear Palsy and Corticobasal Syndrome

Article type: Research Article

Authors: Borroni, Barbara^{a; *} | Del Bo, Roberto^b | Goldwurm, Stefano^c | Archetti, Silvana^d | Bonvicini, Cristian^e | Agosti, Chiara^a | Bigni, Barbara^a | Papetti, Alice^a | Ghezzi, Serena^b | Sacilotto, Giorgio^c | Pezzoli, Gianni^c | Gennarelli, Massimo^{e; f} | Bresolin, Nereo^b | Comi, Giacomo Pietro^b | Padovani, Alessandro^{a; g}

Affiliations: [a] Centre for Aging Brain and Neurodegenerative Disorders, Department of Neurology, University of Brescia, Brescia, Italy | [b] “Dino Ferrari Centre”, Department of Neurological Sciences, University of Milan, I.R.C.C.S. “Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena”, Milan, Italy | [c] Centro Parkinson, Istituti Clinici di Perfezionamento, Milan, Italy | [d] III Laboratory of Analyses, Department of Biotechnology, University of Brescia, Brescia, Italy | [e] Genetic Unit, IRCCS Fatebenefratelli, Brescia, Italy | [f] Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy | [g] Centre for Behavioural Disturbances, Ente Universitario Lombardia Orientale, Brescia, Italy

Correspondence: [*] Correspondence to: Barbara Borroni, M.D., Clinica Neurologica, Università degli Studi di Brescia, Pza Spedali Civili, 1-25100 Brescia, Italy. Tel.: +39 0303995632; Fax: +39 0303995027; E-mail: [email protected].

Note: [] Handling Associate Editor: Amalia Bruni

Abstract: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD). The aim of this study was to evaluate the role of VEGF genetic determinants in PSP and CBS susceptibility. We evaluated a cohort of 687 unrelated Italian subjects, including 117 PSP, 108 CBS, 199 FTD, and 263 healthy controls. Genotype and allele frequencies of three well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, and -1154G/A) were carried out. Genetic analysis revealed the presence of significant changes in terms of genotype and allele distributions in patients compared to healthy controls. A-G-G haplotype (-2578C/A, 1190G/A, -1154G/A) was overrepresented in both PSP (OR=6.64, 95% CI=2.3–19.6, P=0.0003, CGG=reference) and CBS (OR=5.20, 95% CI=1.70–15.9, P=0.003, CGG=reference) compared to healthy subjects. No differences between PSP and CBS and FTD were found, and the A-G-G haplotype was also overrepresented in FTD. Overall, these data suggest that VEGF gene variability represents a susceptibility factor for PSP and CBS. These data argue that additional genes may confer disease risk to PSP and CBS, and to FTD as well, beyond the MAPT tau haplotype. Further studies are warranted.

Keywords: Corticobasal syndrome, frontotemporal dementia, haplotype, polymorphism, progressive supranuclear palsy, vascular endothelial growth factor

DOI: 10.3233/JAD-2010-091615

Journal: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 87-94, 2010