Association of vitamin D receptor gene TaqI polymorphism with Alzheimer's disease in a Southeastern European Caucasian population

Dimitrakis,Efthimios; Katsarou,Martha-Spyridoula; Lagiou,Maria; Papastefanopoulou,Vasiliki; Stanitsa,Evangelia; Spandidos,Demetrios A.; Tsatsakis,Aristidis; Papageorgiou,Socratis; Moutsatsou,Paraskevi; Antoniou,Katerina; Kroupis,Christos; Drakoulis,Nikolaos

doi:10.3892/etm.2022.11271

Association of vitamin D receptor gene TaqI polymorphism with Alzheimer's disease in a Southeastern European Caucasian population

Authors:
- Efthimios Dimitrakis
- Martha-Spyridoula Katsarou
- Maria Lagiou
- Vasiliki Papastefanopoulou
- Evangelia Stanitsa
- Demetrios A. Spandidos
- Aristidis Tsatsakis
- Socratis Papageorgiou
- Paraskevi Moutsatsou
- Katerina Antoniou
- Christos Kroupis
- Nikolaos Drakoulis
View Affiliations

Affiliations: Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece, Department of Clinical Biochemistry, University General Hospital ‘ATTIKON’, 12462 Athens, Greece, Second Department of Neurology, University General Hospital ‘ATTIKON’, 12462 Athens, Greece, Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece, Department of Forensic Sciences and Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece, Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
Published online on: March 22, 2022 https://doi.org/10.3892/etm.2022.11271
Article Number: 341
Copyright: © Dimitrakis et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of vitamin D in Alzheimer's Disease (AD) has been studied over the past years. The results from numerous studies have indicated that the molecular pathways involved in the development of AD are closely related to the molecular pathways of the mechanisms of action of vitamin D. However, only a limited number of studies have described the key role of vitamin D receptor (VDR) in the regulation of the functions of vitamin D and the potential effect of single nucleotide polymorphisms (SNPs) of the VDR gene. Thus, the aim of the present study was to investigate the VDR TaqI polymorphism in relation to AD in a Southeastern European Caucasian (SEC) cohort. Further, the present study aimed to compare the results obtained with those of other AD populations. For this purpose, blood samples from 90 confirmed patients with AD [median age, 74 years; median mini‑mental state examination (MMSE) score of 21; median frontal assessment battery (FAB) score of 10] and 103 healthy controls (median age, 57 years) were analyzed to determine the genotypes of TaqI (rs731236) using quantitative PCR. The frequencies (%) of the TaqI TT, TC and CC genotypes in the controls/patients were 34/48.9, 47.6/41.1 and 18.4/10.0, respectively. Statistically significant differences were observed for the TaqI C allele [odds ratio (OR). 0.54; 95% confidence interval (CI), 0.30‑0.96; P=0.035], the TaqI TT genotype (OR, 1.86; 95% CI, 1.04‑3.32; P=0.035) and the TaqI CC genotype (OR, 0.119; 95% CI, 0.014‑0.995; P=0.032,) in relation to the MMSE score <21 in the patient's group. The TaqI TT allele was found to increase the risk of developing AD by 1.86‑fold in the SEC population, while the TaqI C allele may act protectively, with a 46% lower risk of developing the disease. Patients with the TaqI CC genotype were found to have an 88% less likelihood of developing severe cognitive impairment based on the MMSE score. On the whole, the present study did not confirm the results of previous studies on the VDR TaqI C allele in patients with AD.

View Figures

View References

1	Global Action Plan on the Public Health Response to Dementia 2017-2025. World Health Organization, Geneva, 2017.
2	Orme RP, Middleditch C, Waite L and Fricker RA: The Role of Vitamin D₃ in the development and neuroprotection of midbrain dopamine neurons. Vitam Horm. 100:273–297. 2016.PubMed/NCBI View Article : Google Scholar
3	Wrzosek M, Łukaszkiewicz J, Wrzosek M, Jakubczyk A, Matsumoto H, Piątkiewicz P, Radziwoń-Zaleska M, Wojnar M and Nowicka G: Vitamin D and the central nervous system. Pharmacol Rep. 65:271–278. 2013.PubMed/NCBI View Article : Google Scholar
4	Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, Fried L, Kestenbaum BR, Kuller LH, Langa KM, et al: Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 83:920–928. 2014.PubMed/NCBI View Article : Google Scholar
5	Afzal S, Bojesen SE and Nordestgaard BG: Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia. Alzheimers Dement. 10:296–302. 2014.PubMed/NCBI View Article : Google Scholar
6	Gezen-Ak D, Yilmazer S and Dursun E: Why Vitamin D in Alzheimer's Disease? The Hypothesis. J Alzheimers Dis. 40:257–269. 2014.PubMed/NCBI View Article : Google Scholar
7	Landel V, Annweiler C, Millet P, Morello M and Féron F: Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic benefit is in the D-Tails. J Alzheimers Dis. 53:419–444. 2016.PubMed/NCBI View Article : Google Scholar
8	Mavraki E, Ioannidis P, Tripsianis G, Gioka T, Kolousi M and Vadikolias K: Vitamin D in mild cognitive impairment and Alzheimer's disease. A study in older Greek adults. Hippokratia. 24:120–126. 2020.PubMed/NCBI
9	Gezen-Ak D, Dursun E and Yilmazer S: The effect of Vitamin D treament On Nerve Growth Factor (NGF) Release from Hippocampal Neurons. Noro Psikiyatr Ars. 51:157–162. 2014.PubMed/NCBI View Article : Google Scholar
10	Dursun E, Gezen-Ak D and Yilmazer S: The Influence of Vitamin D treatment on the Inducible Nitric Oxide Synthase (INOS) Expression in Primary Hippocampal Neurons. Noro Psikiyatr Ars. 51:163–168. 2014.PubMed/NCBI View Article : Google Scholar
11	Gradinaru D, Borsa C, Ionescu C, Margina D, Prada GI and Jansen E: Vitamin D status and oxidative stress markers in the elderly with impaired fasting glucose and type 2 diabetes mellitus. Aging Clin Exp Res. 24:595–602. 2012.PubMed/NCBI View Article : Google Scholar
12	Mizwicki MT, Menegaz D, Zhang J, Barrientos-Durán A, Tse S, Cashman JR, Griffin PR and Fiala M: Genomic and nongenomic signaling induced by 1α,25(OH)2-vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages. J Alzheimers Dis. 29:51–62. 2012.PubMed/NCBI View Article : Google Scholar
13	Mizwicki MT, Liu G, Fiala M, Magpantay L, Sayre J, Siani A, Mahanian M, Weitzman R, Hayden EY, Rosenthal MJ, et al: 1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients. J Alzheimers Dis. 34:155–170. 2013.PubMed/NCBI View Article : Google Scholar
14	Gezen-Ak D, Dursun E and Yilmazer S: The effects of vitamin D receptor silencing on the expression of LVSCC-A1C and LVSCC-A1D and the release of NGF in cortical neurons. PLoS One. 6(e17553)2011.PubMed/NCBI View Article : Google Scholar
15	Cui X, Gooch H, Petty A, McGrath JJ and Eyles D: Vitamin D and the brain: Genomic and non-genomic actions. Mol Cell Endocrinol. 453:131–143. 2017.PubMed/NCBI View Article : Google Scholar
16	Gezen-Ak D, Dursun E, Ertan T, Hanagasi H, Gurvit H, Emre M, Eker E, Ozturk M, Engin F and Yilmazer S: Association between Vitamin D receptor gene polymorphism and Alzheimer's disease. Tohoku J Exp Med. 212:275–282. 2007.PubMed/NCBI View Article : Google Scholar
17	Lehmann DJ, Refsum H, Warden DR, Medway C, Wilcock GK and Smith AD: The vitamin D receptor gene is associated with Alzheimer's disease. Neurosci Lett. 504:79–82. 2011.PubMed/NCBI View Article : Google Scholar
18	Esfehani NT, Rahgozar M and Biglarian A: Identification of genetic polymorphism interactions in sporadic Alzheimer's disease using logic regression. Iran Rehabil J. 9:45–50. 2011.
19	Gezen-Ak D, Dursun E, Bilgic B, Hanagasi H, Ertan T, Gurvit H, Emre M, Eker E, Ulutin T, Uysal O and Yilmazer S: Vitamin D receptor gene haplotype is associated with late onset Alzheimer's disease. Tohoku J Exp Med. 228:189–196. 2012.PubMed/NCBI View Article : Google Scholar
20	Khorram Khorshid HR, Gozalpour E, Saliminejad K, Karimloo M, Ohadi M and Kamali K: Vitamin D receptor (VDR) polymorphisms and late-onset Alzheimer's disease: An association study. Iran J Publ Health. 42:1253–1258. 2013.PubMed/NCBI
21	Łaczmański L, Jakubik M, Bednarek-Tupikowska G, Rymaszewska J, Słoka N and Lwow F: Vitamin D receptor gene polymorphisms in Alzheimer's disease patients. Exp Gerontol. 69:142–147. 2015.PubMed/NCBI View Article : Google Scholar
22	Oliveira ACR, Magalhães CA, Loures CMG, Fraga VG, de Souza LC, Guimarães HC, Cintra MTG, Bicalho MA, Sousa MCR, Silveira JN, et al: BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline. Arq Neuropsiquiatr. 76:760–766. 2018.PubMed/NCBI View Article : Google Scholar
23	Poduslo SE and Yin X: Chromosome 12 and late-onset Alzheimer's disease. Neurosci Lett. 310:188–190. 2001.PubMed/NCBI View Article : Google Scholar
24	Gezen-Ak D and Dursun E: Molecular basis of vitamin D action in neurodegeneration: The story of a team perspective. Hormones (Athens). 18:17–21. 2019.PubMed/NCBI View Article : Google Scholar
25	Gezen-Ak D, Atasoy IL, Candaş E, Alaylioglu M, Yılmazer S and Dursun E: Vitamin D receptor regulates amyloid beta 1-42 production with protein disulfide isomerase A3. ACS Chem Neurosci. 8:2335–2346. 2017.PubMed/NCBI View Article : Google Scholar
26	Sutherland MK, Somerville MJ, Yoong LK, Bergeron C, Haussler MR and McLachlan DR: Reduction of vitamin D hormone receptor mRNA levels in Alzheimer as compared to huntington hippocampus: Correlation with calbindin-28k mRNA levels. Brain Res Mol Brain Res. 13:239–250. 1992.PubMed/NCBI View Article : Google Scholar
27	Landel V, Millet P, Baranger K, Loriod B and Féron F: Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer's disease. Mol Neurodegener. 11(22)2016.PubMed/NCBI View Article : Google Scholar
28	Gubandru M, Margina D, Tsitsimpikou C, Goutzourelas N, Tsarouhas K, Ilie M, Tsatsakis AM and Kouretas D: Alzheimer's disease treated patients showed different patterns for oxidative stress and inflammation markers. Food Chem Toxicol. 61:209–214. 2013.PubMed/NCBI View Article : Google Scholar
29	Nitulescu GM, Van De Venter M, Nitulescu G, Ungurianu A, Juzenas P, Peng Q, Olaru OT, Gradinaru D, Tsatsakis A, Tsoukalas D, et al: The Akt pathway in oncology therapy and beyond (Review). Int J Oncol. 53:2319–2331. 2018.PubMed/NCBI View Article : Google Scholar
30	Zaulkffali AS, Md Razip NN, Syed Alwi SS, Abd Jalil A, Abd Mutalib MS, Gopalsamy B, Chang SK, Zainal Z, Ibrahim NN, Zakaria ZA and Khaza'ai H: Vitamins D and E stimulate the PI3K-AKT signalling pathway in insulin-resistant SK-N-SH neuronal cells. Nutrients. 11(2525)2019.PubMed/NCBI View Article : Google Scholar
31	Zhang D, Wang L, Zhang R and Li S: Association of vitamin D receptor gene polymorphisms and the risk of multiple sclerosis: A meta-analysis. Arch Med Res. 50:350–361. 2019.PubMed/NCBI View Article : Google Scholar
32	Niu MY, Wang L and Xie AM: ApaI, BsmI, FokI, and TaqI polymorphisms in the vitamin D receptor gene and Parkinson's disease. Chin Med J (Engl). 128:1809–1814. 2015.PubMed/NCBI View Article : Google Scholar
33	Papasavva M, Vikelis M, Siokas V, Katsarou MS, Dermitzakis E, Raptis A, Dardiotis E and Drakoulis N: VDR gene polymorphisms and cluster headache susceptibility: Case-control study in a Southeastern European caucasian population. J Mol Neurosci. 72:382–392. 2022.PubMed/NCBI View Article : Google Scholar
34	Geng J, Zhang J, Yao F, Liu X, Liu J and Huang Y: A systematic review and meta-analysis of the associations of vitamin D receptor genetic variants with two types of most common neurodegenerative disorders. Aging Clin Exp Res. 32:21–27. 2020.PubMed/NCBI View Article : Google Scholar
35	Mun MJ, Kim MS, Kim JH and Jang WC: A TaqI polymorphism of vitamin D receptor is associated with Alzheimer's disease in Korean population: A case-control study. Int J Clin Exp Med. 9:19268–19279. 2016.
36	Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp RG and Van Heemst D: VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging. 30:466–473. 2009.PubMed/NCBI View Article : Google Scholar