Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort

Issue title: Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

Guest editors: K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny and Ricardo B. Maccioni

Article type: Research Article

Authors: Arévalo, Nohela B.^{a; i} | Castillo-Godoy, Daniela P.^a | Espinoza-Fuenzalida, Italo^a | Rogers, Nicole K.^b | Farias, Gonzalo^{c; d} | Delgado, Carolina^c | Henriquez, Mauricio^{e; f} | Herrera, Luisaⁱ | Behrens, María Isabel^{b; c; d; j; *} | SanMartín, Carol D.^{a; c; g; h; *}

Affiliations: [a] Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile | [b] Departamento de Neurociencia, Facultad de Medicina, Universidad de Chile, Santiago, Chile | [c] Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santiago, Chile | [d] Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago, Chile | [e] Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile | [f] Red para el Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile | [g] Escuela de Tecnologia Médica, Facultad de Ciencias, Universidad Mayor, Santiago, Chile | [h] Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile | [i] Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile | [j] Departamento de Neurología y Psiquiatría, Clínica Alemana de Santiago, Santiago, Chile

Correspondence: [*] Correspondence to: Carol D. SanMartín, PhD, Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Camino La Piramide 5750, Huechuraba, Santiago de Chile, 8580000. Tel.: +56 2 25189245; E-mail: [email protected]. and María Isabel Behrens, MD, PhD, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santos Dumontt 999, Independencia, Santiago, Chile, 8380456. Tel.: +56 2 29788260; E-mail: [email protected].

Abstract: Background:Amyloid-β peptide (Aβ) deposition in Alzheimer’s disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. Objective:To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aβ-transporters in peripheral blood mononuclear cells (PBMCs). Methods:VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aβ-transporters were evaluated in subgroups by qPCR. Results:Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aβ-transporters in both groups. Conclusion:We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

Keywords: Alzheimer’s disease, ATP binding cassette transporter, cognitive dysfunction, receptor for advanced glycation end products (RAGE), single nucleotide polymorphism, vitamin D, vitamin D receptor

DOI: 10.3233/JAD-201031

Journal: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S283-S297, 2021