Abstract
The CR1 gene has been widely studied in Alzheimer’s disease (AD), since its first association with the disease in 2009. Even after 11 years of this discovery, the role of this gene in AD has not yet been fully elucidated and the association of its variants was not validated in Latin American populations. We genotyped five CR1 single nucleotide polymorphisms (SNPs rs6656401, rs3849266, rs2274567, rs4844610, and rs12034383) in up to 162 AD patients and 137 controls through PCR-SSP and iPLEX MassARRAY Platform (Sequenom), and measured soluble CR1 (sCR1) levels in plasma of 40 AD patients and 39 controls with an enzyme-linked immunosorbent assay (ELISA). Homozygosity for haplotype rs3849266*C_rs2274567*A (CA/CA genotype) was associated with susceptibility to AD (OR = 2.94, p = 0.018). Patients presented higher sCR1 levels in plasma than controls (p = 0.038). Furthermore, patients that carry the rs2274567*G allele (p.1208Arg) presented higher sCR1 levels than A/A (p.1208His/His) homozygotes (p = 0.036). This is the first study to validate the association of CR1 polymorphisms with late-onset Alzheimer’s disease, as well as to evaluate sCR1 levels in a Latin American population. SNPs present in the regulatory and coding regions of this gene may be playing a key role in the observed association, probably by interfering in Aβ plaques clearance. Inhibition may be due to the increase in local sCR1 levels observed in patients, which may result from polymorphisms leading to larger isoforms of CR1 and/or structural alterations of the protein that makes it less functional, as well as increased vesiculation of the molecules.
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Acknowledgments
We are deeply grateful for the patients’ participation in this study and thank the staff of the Polymorphism and Linkage Laboratory/UFPR for their assistance in DNA extraction.
Funding
This work was supported by grants of Fundação Araucária (FA-protocol 39894.413.43926.1904/2013 and 116/2018, protocol 50.530), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES-40001016006P1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-314288/2018-0). The funding agencies had no role in study design, in the collection, analysis and interpretation of data, in the writing of the letter, and in the decision to submit it for publication.
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Conceptualization: GCK and ABWB; methodology: GCK, AAHA, LCO, and RMN; formal analysis and investigation: GCK and AAHA; writing—original draft preparation: GCK; writing—review and editing: all the authors; funding acquisition: MLEP, RLRS, and ABWB; supervision: ABWB. All authors read and approved the final manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Research Ethics Committee of the Health Sciences Sector (Federal University of Paraná) (CAAE: 55965316.1.0000.0102), according to Resolution 466/2012 of the National Health Council and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Gabriela Canalli Kretzschmar and Angela Adriane Hanel Antoniazzi are first authors.
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Kretzschmar, G.C., Antoniazzi, A.A.H., Oliveira, L.C. et al. First Report of CR1 Polymorphisms and Soluble CR1 Levels Associated with Late Onset Alzheimer’s Disease (LOAD) in Latin America. J Mol Neurosci 70, 1338–1344 (2020). https://doi.org/10.1007/s12031-020-01547-2
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DOI: https://doi.org/10.1007/s12031-020-01547-2