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

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.

Associations of vitamin D receptor polymorphisms with risk of Alzheimer’s disease, Parkinson’s disease, and mild cognitive impairment: a systematic review and meta-analysis

“…Functionally, the neuroprotective effects of estrogens in neural cells against amyloid β-induced neurotoxicity are based on amyloid degradation or other molecular mechanisms (Yagyu et al, 2002;Marin et al, 2003;Quintanilla et al, 2005;Amtul et al, 2010). A cohort study indicated female patients with poor cognitive performance is associated with insufficient levels of VitD, whereas no such association was observed in male patients (Arévalo et al, 2021). The possible hypothesis is that body fat in women is greater than in men, and in this way circulating vitamin D can be stored in adipose tissue and, given its lipophilic characteristics, would be less available in plasma (Oliveira et al, 2018).…”

“…Additionally, some underlying genes, such as CYP27A1 and CYP27B1, could affect the function of BsmI, ApaI, and TaqI (Cheng et al, 2004;Uitterlinden et al, 2004). The ApaI genotype was found to affects the mRNA expression of target gene, including P-gp, LRP1, and RAGE, facilitating brain Aß aggregation (Arévalo et al, 2021). The Apa1 and Taq1 polymorphisms have potential interaction with interleukin-10 (IL-10) SNP, suggesting that the candidate gene may have superimposed effects with the Apa1 or Taq1 in the AD progression (Lehmann et al, 2011).…”

“…After carefully reviewing the full texts, we performed a secondary screening and eliminated 257 articles due to other disease (n = 231), insufficient information (n = 3), other genes and VDR gene polymorphisms (n = 23). A total of 30 studies covering 81 studies were retained for this meta-analysis (Luedecking-Zimmer et al, 2003;Kim et al, 2005;Gezen-Ak et al, 2007Lehmann et al, 2011;Han et al, 2012;Khorram Khorshid et al, 2013;Liu et al, 2013;Lv et al, 2013;Török et al, 2013;Petersen et al, 2014;Gatto et al, 2015;Łaczmański et al, 2015;Zhou et al, 2015;Kang et al, 2016;Mohammadzadeh and Pazhouhesh, 2016;Mun et al, 2016;Meamar et al, 2017;Tanaka et al, 2017;Oliveira et al, 2018;Hu et al, 2020;Agliardi et al, 2021;Arévalo et al, 2021;Agúndez et al, 2022;Dimitrakis et al, 2022a,b;Kamyshna et al, 2022;Redenšek et al, 2022;Zhang et al, 2022).…”

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

“…Castillo-Mendieta et al [18] report the potential of plasma biomarkers of neuropathological signs of AD as a cost-effective approach to identifying individuals at risk for AD in a sample of Mexican AD patients. Arévalo et al [19] propose a role for vitamin D receptor polymorphisms in MCI and AD in a Chilean sample and include studies in peripheral blood mononuclear cells. Ayala-Gross et al [20] report the results of cross-sectional analyses that suggest that chronic dysregulation of cortisol secretion may contribute to cognitive impairment using data from PAHO/WHO agencies.…”