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01-03-2017 | Original Paper

GC and VDR SNPs and Vitamin D Levels in Parkinson’s Disease: The Relevance to Clinical Features

Authors: Duygu Gezen-Ak, Merve Alaylıoğlu, Gençer Genç, Ayşegül Gündüz, Esin Candaş, Başar Bilgiç, İrem L. Atasoy, Hülya Apaydın, Güneş Kızıltan, Hakan Gürvit, Haşmet Hanağası, Sibel Ertan, Selma Yılmazer, Erdinç Dursun

Published in: NeuroMolecular Medicine | Issue 1/2017

Abstract

Vitamin D deficiency is suggested to be associated with Parkinson’s disease (PD). Our aim was to investigate the serum 25-hydroxyvitamin D₃ (25OHD) levels of PD patients in Turkish cohort, to investigate any association of vitamin D binding protein (GC) genotypes with PD due to the significant role of GC in vitamin D transport, to determine whether vitamin D receptor (VDR) haplotype that we previously demonstrated to be a risk haplotype for AD is also a common haplotype for PD and to investigate any relevant consequence of serum 25OHD levels, GC or VDR genotypes on clinical features of PD. Three hundred eighty-two PD patients and 242 healthy subjects were included in this study. The serum 25OHD levels were investigated by CLIA, and GC and VDR SNPs were evaluated with LightSnip. Our results indicated a strong relationship between low serum 25OHD levels and PD (p < 0.001). rs7041 of GC and ApaI of VDR were associated with the PD risk (p < 0.05). Minor allele carriers for BsmI of VDR gene in both PD patients and healthy subjects had significantly higher levels of serum 25OHD (p < 0.05). The homozygous major allele carriers for rs2282679, rs3755967 and rs2298850 of GC gene in PD patients with slower progression had significantly higher levels of serum 25OHD (p < 0.05). Minor allele carriers for FokI of VDR gene were more frequent in patients with advanced-stage PD (p < 0.05). Consequently, this is the first study demonstrating GC gene as a risk factor for PD. The relationship between PD’s clinical features and low 25OHD or risk genotypes might have effects on PD independently.

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Abdi, F., Quinn, J. F., Jankovic, J., McIntosh, M., Leverenz, J. B., Peskind, E., et al. (2006). Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. Journal of Alzheimer’s Disease, 9(3), 293–348.PubMed

Alkan, C., Kavak, P., Somel, M., Gokcumen, O., Ugurlu, S., Saygi, C., et al. (2014). Whole genome sequencing of Turkish genomes reveals functional private alleles and impact of genetic interactions with Europe, Asia and Africa. BMC Genomics, 15, 963. doi:10.1186/1471-2164-15-963.CrossRefPubMedPubMedCentral

Annweiler, C., Schott, A. M., Allali, G., Bridenbaugh, S. A., Kressig, R. W., Allain, P., et al. (2010). Association of vitamin D deficiency with cognitive impairment in older women: Cross-sectional study. Neurology, 74(1), 27–32.CrossRefPubMed

Beecham, G. W., Martin, E. R., Li, Y. J., Slifer, M. A., Gilbert, J. R., Haines, J. L., et al. (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. The American Journal of Human Genetics, 84, 35–43.CrossRefPubMed

Beydoun, M. A., Ding, E. L., Beydoun, H. A., Tanaka, T., Ferrucci, L., & Zonderman, A. B. (2012). Vitamin D receptor and megalin gene polymorphisms and their associations with longitudinal cognitive change in US adults. The American Journal of Clinical Nutrition, 95, 163–178.CrossRefPubMed

Bhan, I. (2014). Vitamin d binding protein and bone health. International Journal of Endocrinology, 2014, 561214. doi:10.1155/2014/561214.CrossRefPubMedPubMedCentral

Bishnoi, R. J., Palmer, R. F., & Royall, D. R. (2015). Vitamin D binding protein as a serum biomarker of Alzheimer’s disease. Journal of Alzheimer’s Disease, 43(1), 37–45. doi:10.3233/JAD-140042.PubMed

Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C., et al. (1998). Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature Genetics, 19, 357–360.CrossRefPubMed

Butler, M. W., Burt, A., Edwards, T. L., Zuchner, S., Scott, W. K., Martin, E. R., et al. (2011). Vitamin D receptor gene as a candidate gene for Parkinson disease. Annals of Human Genetics, 75(2), 201–210.CrossRefPubMedPubMedCentral

Cass, W. A., Peters, L. E., Fletcher, A. M., & Yurek, D. M. (2012). Evoked dopamine overflow is augmented in the striatum of calcitriol treated rats. Neurochemistry International, 60(2), 186–191. doi:10.1016/j.neuint.2011.11.010.CrossRefPubMed

Cherniack, E. P., Florez, H., Roos, B. A., Troen, B. R., & Levis, S. (2008). Hypovitaminosis D in the elderly: From bone to brain. The Journal of Nutrition Health and Aging, 12(6), 366–373.CrossRef

Delanghe, J. R., Speeckaert, R., & Speeckaert, M. M. (2015). Behind the scenes of vitamin D binding protein: More than vitamin D binding. Best Practice & Research Clinical Endocrinology & Metabolism, 29(5), 773–786. doi:10.1016/j.beem.2015.06.006.CrossRef

Dursun, E., Gezen-Ak, D., & Yilmazer, S. (2011). A novel perspective for Alzheimer’s disease: Vitamin D receptor suppression by amyloid-beta and preventing the amyloid-beta induced alterations by vitamin D in cortical neurons. Journal of Alzheimer’s Disease, 23(2), 207–219. doi:10.3233/JAD-2010-101377.PubMed

Evatt, M. L., DeLong, M. R., Khazai, N., Rosen, A., Triche, S., & Tangpricha, V. (2008). Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Archives of Neurology, 65(10), 1348–1352.CrossRefPubMedPubMedCentral

Eyles, D. W., Burne, T. H., & McGrath, J. J. (2013). Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Frontiers in Neuroendocrinology, 34(1), 47–64. doi:10.1016/j.yfrne.2012.07.001.CrossRefPubMed

Gatto, N. M., Sinsheimer, J. S., Cockburn, M., Escobedo, L. A., Bordelon, Y., & Ritz, B. (2015). Vitamin D receptor gene polymorphisms and Parkinson’s disease in a population with high ultraviolet radiation exposure. Journal of the Neurological Sciences, 352(1–2), 88–93. doi:10.1016/j.jns.2015.03.043.CrossRefPubMedPubMedCentral

Gezen-Ak, D., Dursun, E., Bilgic, B., Hanagasi, H., Ertan, T., Gurvit, H., et al. (2012). Vitamin D receptor gene haplotype is associated with late-onset Alzheimer’s disease. The Tohoku Journal of Experimental Medicine, 228(3), 189–196.CrossRefPubMed

Gezen-Ak, D., Dursun, E., Ertan, T., Hanagasi, H., Gurvit, H., Emre, M., et al. (2007). Association between vitamin D receptor gene polymorphism and Alzheimer’s disease. The Tohoku Journal of Experimental Medicine, 212(3), 275–282.CrossRefPubMed

Gezen-Ak, D., Dursun, E., & Yilmazer, S. (2011). 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(3), e17553. doi:10.1371/journal.pone.0017553.CrossRefPubMedPubMedCentral

Gezen-Ak, D., Yilmazer, S., & Dursun, E. (2014). Why vitamin D in Alzheimer’s disease? The hypothesis. Journal of Alzheimer’s Disease, 40(2), 257–269. doi:10.3233/JAD-131970.PubMed

Goetz, C. G., Poewe, W., Rascol, O., Sampaio, C., Stebbins, G. T., Counsell, C., et al. (2004). Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. Movement Disorders, 19(9), 1020–1028. doi:10.1002/mds.20213.CrossRefPubMed

Han, X., Xue, L., Li, Y., Chen, B., & Xie, A. (2012). Vitamin D receptor gene polymorphism and its association with Parkinson’s disease in Chinese Han population. Neuroscience Letters, 525(1), 29–33. doi:10.1016/j.neulet.2012.07.033.CrossRefPubMed

Hekimsoy, Z., Dinc, G., Kafesciler, S., Onur, E., Guvenc, Y., Pala, T., et al. (2010). Vitamin D status among adults in the Aegean region of Turkey. BMC Public Health, 10, 782. doi:10.1186/1471-2458-10-782.CrossRefPubMedPubMedCentral

Hoehn, M. M., & Yahr, M. D. (1967). Parkinsonism: Onset, progression and mortality. Neurology, 17(5), 427–442.CrossRefPubMed

Hollenbach, E., Ackermann, S., Hyman, B. T., & Rebeck, G. W. (1998). Confirmation of an association between a polymorphism in exon 3 of the low-density lipoprotein receptor-related protein gene and Alzheimer’s disease. Neurology, 50, 1905–1907.CrossRefPubMed

Kim, J. S., Kim, Y. I., Song, C., Yoon, I., Park, J. W., Choi, Y. B., et al. (2005). Association of vitamin D receptor gene polymorphism and Parkinson’s disease in Koreans. Journal of Korean Medical Science, 20(3), 495–498.CrossRefPubMedPubMedCentral

Knekt, P., Kilkkinen, A., Rissanen, H., Marniemi, J., Sääksjärvi, K., & Heliövaara, M. (2010). Serum vitamin D and the risk of Parkinson disease. Archives of Neurology, 67(7), 808–811.CrossRefPubMedPubMedCentral

Kostner, K., Denzer, N., Muller, C. S., Klein, R., Tilgen, W., & Reichrath, J. (2009). The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: A review of the literature. Anticancer Research, 29(9), 3511–3536.PubMed

Kumar, P. T., Antony, S., Nandhu, M. S., Sadanandan, J., Naijil, G., & Paulose, C. S. (2011). Vitamin D₃ restores altered cholinergic and insulin receptor expression in the cerebral cortex and muscarinic M3 receptor expression in pancreatic islets of streptozotocin induced diabetic rats. The Journal of Nutritional Biochemistry, 22(5), 418–425. doi:10.1016/j.jnutbio.2010.03.010.CrossRefPubMed

Kuningas, M., Mooijaart, S. P., Jolles, J., Slagboom, P. E., Westendorp, R. G. J., & Van Heemst, D. (2009). VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiology of Aging, 30, 466–473.CrossRefPubMed

Lehmann, D. J., Refsum, H., Warden, D. R., Medway, C., Wilcock, G. K., & Smith, D. A. (2011). The vitamin D receptor gene is associated with Alzheimer’s disease. Neuroscience Letters, 504, 79–82.CrossRefPubMed

Lin, C. H., Chen, K. H., Chen, M. L., Lin, H. I., & Wu, R. M. (2014). Vitamin D receptor genetic variants and Parkinson’s disease in a Taiwanese population. Neurobiology of Aging, 35(5), 1212.e11–1212.e13. doi:10.1016/j.neurobiolaging.2013.10.094.CrossRef

Liu, H. X., Han, X., Zheng, X. P., Li, Y. S., & Xie, A. M. (2013). Association of vitamin D receptor gene polymorphisms with Parkinson disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 30(1), 13–16. doi:10.3760/cma.j.issn.1003-9406.2013.01.004.PubMed

Llewellyn, D. J., Lang, I. A., Langa, K. M., Muniz-Terrera, G., Phillips, C. L., Cherubini, A., et al. (2010). Vitamin D and risk of cognitive decline in elderly persons. Archives of Internal Medicine, 170(13), 1135–1141.CrossRefPubMedPubMedCentral

Llewellyn, D. J., Langa, K. M., & Lang, I. A. (2009). Serum 25-hydroxyvitamin D concentration and cognitive impairment. Journal of Geriatric Psychiatry and Neurology, 22(3), 188–195.CrossRefPubMed

Luedecking-Zimmer, E., DeKosky, S., Nebes, R., & Kamboh, I. (2003). Association of the 3′UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer’s disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 117, 114–117.CrossRef

Lurie, G., Wilkens, L. R., Thompson, P. J., McDuffie, K. E., Carney, M. E., Terada, K. Y., et al. (2007). Vitamin D receptor gene polymorphisms and epithelial ovarian cancer risk. Cancer Epidemiol Biomarkers & Prevention, 16(12), 2566–2571. doi:10.1158/1055-9965.EPI-07-0753.CrossRef

Lv, Z., Tang, B., Sun, Q., Yan, X., & Guo, J. (2013). Association study between vitamin d receptor gene polymorphisms and patients with Parkinson disease in Chinese Han population. International Journal of Neuroscience, 123(1), 60–64. doi:10.3109/00207454.2012.726669.CrossRefPubMed

McCann, J., & Ames, B. N. (2008). Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? The FASEB Journal, 22, 982–1001.CrossRefPubMed

Meamar, R., Shaabani, P., Tabibian, S. R., Aghaye Ghazvini, M. R., & Feizi, A. (2015). The effects of uric Acid, serum vitamin D₃, and their interaction on Parkinson’s disease severity. Parkinson’s Disease, 2015, 463483. doi:10.1155/2015/463483.PubMedPubMedCentral

Moghaddasi, M., Mamarabadi, M., & Aghaii, M. (2013). Serum 25-hydroxyvitamin D3 concentration in Iranian patients with Parkinson’s disease. Iranian Journal of Neurology, 12(2), 56–59.PubMedPubMedCentral

Moon, M., Song, H., Hong, H. J., Nam, D. W., Cha, M. Y., Oh, M. S., et al. (2013). Vitamin D-binding protein interacts with Abeta and suppresses Abeta-mediated pathology. Cell Death and Differentiation, 20(4), 630–638. doi:10.1038/cdd.2012.161.CrossRefPubMed

Peeyush Kumar, T., Paul, J., Antony, S., & Paulose, C. S. (2011). Expression of cholinergic, insulin, vitamin D receptors and GLUT 3 in the brainstem of streptozotocin induced diabetic rats: Effect of treatment with vitamin D(3). Neurochemical Research, 36(11), 2116–2126. doi:10.1007/s11064-011-0536-9.CrossRefPubMed

Peeyush, K. T., Savitha, B., Sherin, A., Anju, T. R., Jes, P., & Paulose, C. S. (2010). Cholinergic, dopaminergic and insulin receptors gene expression in the cerebellum of streptozotocin-induced diabetic rats: Functional regulation with vitamin D₃ supplementation. Pharmacology, Biochemistry and Behavior, 95(2), 216–222. doi:10.1016/j.pbb.2010.01.008.CrossRefPubMed

Petersen, M. S., Bech, S., Christiansen, D. H., Schmedes, A. V., & Halling, J. (2014). The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson’s disease in the Faroe Islands. Neuroscience Letters, 561, 74–79. doi:10.1016/j.neulet.2013.12.053.CrossRefPubMed

Pludowski, P., Grant, W. B., Bhattoa, H. P., Bayer, M., Povoroznyuk, V., Rudenka, E., et al. (2014). Vitamin D status in central Europe. International Journal of Endocrinology, 2014, 589587. doi:10.1155/2014/589587.CrossRefPubMedPubMedCentral

Poduslo, S. E., & Yin, X. (2001). Chromosome 12 and late onset Alzheimer’s disease. Neuroscience Letters, 310, 188–190.CrossRefPubMed

Sachs, M. C., Shoben, A., Levin, G. P., Robinson-Cohen, C., Hoofnagle, A. N., Swords-Jenny, N., et al. (2013). Estimating mean annual 25-hydroxyvitamin D concentrations from single measurements: The Multi-Ethnic Study of Atherosclerosis. American Journal of Clinical Nutrition, 97(6), 1243–1251. doi:10.3945/ajcn.112.054502.CrossRefPubMedPubMedCentral

Sato, Y., Honda, Y., Iwamoto, J., Kanoko, T., & Satoh, K. (2005). Abnormal bone and calcium metabolism in immobilized Parkinson’s disease patients. Movement Disorders, 20, 1598–1603.CrossRefPubMed

Sato, Y., Kaji, M., Tsuru, T., & Oizumi, K. (2001). Risk factors for hip fracture among elderly patients with Parkinson’s disease. Journal of the Neurological Sciences, 182, 89–93.CrossRefPubMed

Sato, Y., Kikuyama, M., & Oizumi, K. (1997). High prevalence of vitamin D deficiency and reduced bone mass in Parkinson’s disease. Neurology, 49, 1273–1278.CrossRefPubMed

Smith, M. P., Fletcher-Turner, A., Yurek, D. M., & Cass, W. A. (2006). Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochemical Research, 31(4), 533–539. doi:10.1007/s11064-006-9048-4.CrossRefPubMed

Sonnenberg, J., Luine, V. N., Krey, L. C., & Christakos, S. (1986). 1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei. Endocrinology, 118(4), 1433–1439.CrossRefPubMed

Suzuki, M., Yoshioka, M., Hashimoto, M., Murakami, M., Kawasaki, K., Noya, M., et al. (2012). 25-Hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson’s disease. Movement Disorders, 27(2), 264–271. doi:10.1002/mds.24016.CrossRefPubMed

Suzuki, M., Yoshioka, M., Hashimoto, M., Murakami, M., Noya, M., Takahashi, D., et al. (2013). Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease. American Journal of Clinical Nutrition, 97(5), 1004–1013. doi:10.3945/ajcn.112.051664.CrossRefPubMed

Torok, R., Torok, N., Szalardy, L., Plangar, I., Szolnoki, Z., Somogyvari, F., et al. (2013). Association of vitamin D receptor gene polymorphisms and Parkinson’s disease in Hungarians. Neuroscience Letters, 551, 70–74. doi:10.1016/j.neulet.2013.07.014.CrossRefPubMed

Uitterlinden, A. G., Fang, Y., Van Meurs, J. B., Pols, H. A., & Van Leeuwen, J. P. (2004). Genetics and biology of vitamin D receptor polymorphisms. Gene, 338(2), 143–156.CrossRefPubMed

van der Meer, I. M., Middelkoop, B. J., Boeke, A. J., & Lips, P. (2011). Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: An overview. Osteoporosis International, 22(4), 1009–1021. doi:10.1007/s00198-010-1279-1.CrossRefPubMed

Wang, L., Hara, K., Van Baaren, J. M., Price, J. C., Beecham, G. W., Gallins, P. J., et al. (2012). Vitamin D receptor and Alzheimer’s disease: A genetic and functional study. Neurobiology of Aging, 33(8), 1844.e1–1844.e9. doi:10.1016/j.neurobiolaging.2011.12.038.CrossRef

Wang, T. J., Zhang, F., Richards, J. B., Kestenbaum, B., van Meurs, J. B., Berry, D., et al. (2010). Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet, 376(9736), 180–188. doi:10.1016/S0140-6736(10)60588-0.CrossRefPubMedPubMedCentral

Wilkins, C. H., Sheline, Y. I., Roe, C. M., Birge, S. J., & Morris, J. C. (2006). Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. The American Journal of Geriatric Psychiatry, 14, 1032–1040.CrossRefPubMed

Zhang, J., Sokal, I., Peskind, E. R., Quinn, J. F., Jankovic, J., Kenney, C., et al. (2008). CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. American Journal of Clinical Pathology, 129(4), 526–529. doi:10.1309/W01Y0B808EMEH12L.CrossRefPubMedPubMedCentral

Title: GC and VDR SNPs and Vitamin D Levels in Parkinson’s Disease: The Relevance to Clinical Features
Authors: Duygu Gezen-Ak
Merve Alaylıoğlu
Gençer Genç
Ayşegül Gündüz
Esin Candaş
Başar Bilgiç
İrem L. Atasoy
Hülya Apaydın
Güneş Kızıltan
Hakan Gürvit
Haşmet Hanağası
Sibel Ertan
Selma Yılmazer
Erdinç Dursun
Publication date: 01-03-2017
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 1/2017
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-016-8415-9

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GC and VDR SNPs and Vitamin D Levels in Parkinson’s Disease: The Relevance to Clinical Features

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At a glance: The ONWARDS insulin icodec trials

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