Objective: The aim was to compare the vitamin D levels in patients with Graves disease (GD) with the general population and to correlate the vitamin D levels with laboratory and clinical parameters in GD. Moreover, we examined the genetic variation in genes involved in the vitamin D metabolism and their association with GD. Methods: The levels of vitamin D were compared in 292 patients with newly diagnosed GD and 2,305 controls. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1-α-hydroxylase (CYP27B1) were examined for association with GD and/or Graves ophthalmopathy (GO) in 708 patients and 1,178 controls. Results: Patients with GD had significantly lower vitamin D levels compared to controls (55.0 ± 23.2 vs. 87.2 ± 27.6 nmol/L, p < 0.001). In patients with GD (n = 219), there was no association between the levels of vitamin D at diagnosis and free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin receptor antibodies (TRAb), GO at diagnosis, or relapse after terminating treatment with antithyroid drugs. Two SNPs in VDR were associated with GD: rs10735810 (OR = 1.36, 95% CI: 1.02–1.36, p = 0.02) and rs1544410 (OR = 1.47, 95% CI: 1.03–1.47, p = 0.02). There was no difference in the mean vitamin D level between genotypes in either rs10735810 or rs154410. Conclusions: Patients with GD had lower vitamin D levels compared to the general population; however, the vitamin D levels did not affect the laboratory or clinical parameters of GD. SNPs in the VDR influenced the risk of GD through mechanisms other than reducing the vitamin D levels.

1.
Kmiec P, Sworczak K: Vitamin D in thyroid disorders. Exp Clin Endocrinol Diabetes 2015; 123: 386–393.
2.
Inoue N, Watanabe M, Ishido N, Katsumata Y, Kagawa T, Hidaka Y, Iwatani Y: The functional polymorphisms of VDR, GC and CYP2R1 are involved in the pathogenesis of autoimmune thyroid diseases. Clin Exp Immunol 2014; 178: 262–269.
3.
Kurylowicz A, Badenhoop K: CYP27B1 gene polymorphism is associated with Graves’ disease in a Polish population study. Thyroid 2005; 15: 1107–1108.
4.
Abd El Gawad SS, Abdul Samee ER, Metwali AA, Abd El Gawad MS: Vitamin D receptor gene polymorphism and its association with 1,25-dihydroxyvitamin D3 in patients with Graves disease in an Egyptian population: a pilot study. Endocr Pract 2012; 18: 132–139.
5.
Feng M, Li H, Chen SF, Li WF, Zhang FB: Polymorphisms in the vitamin D receptor gene and risk of autoimmune thyroid diseases: a meta-analysis. Endocrine 2013; 43: 318–326.
6.
Jolliffe DA, Walton RT, Griffiths CJ, Martineau AR: Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: review of genetic association studies. J Steroid Biochem Mol Biol 2016; 164: 18–29.
7.
Zhou H, Xu C, Gu M: Vitamin D receptor (VDR) gene polymorphisms and Graves’ disease: a meta-analysis. Clin Endocrinol 2009; 70: 938–945.
8.
Yamashita H, Noguchi S, Takatsu K, Koike E, Murakami T, Watanabe S, Uchino S, Yama­shita H, Kawamoto H: High prevalence of vitamin D deficiency in Japanese female patients with Graves’ disease. Endocr J 2001; 48: 63–69.
9.
Ma J, Wu D, Li C, Fan C, Chao N, Liu J, Li Y, Wang R, Miao W, Guan H, Shan Z, Teng W: Lower Serum 25-hydroxyvitamin D level is associated with 3 types of autoimmune thyroid diseases. Medicine 2015; 94:e1639.
10.
Wang J, Lv S, Chen G, Gao C, He J, Zhong H, Xu Y: Meta-analysis of the association between vitamin D and autoimmune thyroid disease. Nutrients 2015; 7: 2485–2498.
11.
Xu MY, Cao B, Yin J, Wang DF, Chen KL, Lu QB: Vitamin D and Graves’ disease: a meta-analysis update. Nutrients 2015; 7: 3813–3827.
12.
Zhang H, Liang L, Xie Z: Low vitamin D status is associated with increased thyrotropin-receptor antibody titer in Graves disease. Endocr Pract 2015; 21: 258–263.
13.
Yasuda T, Okamoto Y, Hamada N, Miyashita K, Takahara M, Sakamoto F, Miyatsuka T, Kitamura T, Katakami N, Kawamori D, Otsuki M, Matsuoka TA, Kaneto H, Shimomura I: Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves’ disease. Endocrine 2012; 42: 739–741.
14.
Li X, Wang G, Lu Z, Chen M, Tan J, Fang X: Serum 25-hydroxyvitamin D predict prognosis in radioiodine therapy of Graves’ disease. J Endocrinol Invest 2015; 38: 753–759.
15.
Yasuda T, Okamoto Y, Hamada N, Miyashita K, Takahara M, Sakamoto F, Miyatsuka T, Kitamura T, Katakami N, Kawamori D, Otsuki M, Matsuoka TA, Kaneto H, Shimomura I: Serum vitamin D levels are decreased in patients without remission of Graves’ disease. Endocrine 2013; 43: 230–232.
16.
Kawakami-Tani T, Fukawa E, Tanaka H, Abe Y, Makino I: Effect of 1 α-hydroxyvitamin D3 on serum levels of thyroid hormones in hyperthyroid patients with untreated Graves’ disease. Metabolism 1997; 46: 1184–1188.
17.
Planck T, Shahida B, Sjogren M, Groop L, Hallengren B, Lantz M: Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves’ disease and ophthalmopathy. Thyroid 2014; 24: 1156–1161.
18.
Manjer J, Carlsson S, Elmstahl S, Gullberg B, Janzon L, Lindstrom M, Mattisson I, Berglund G: The Malmö Diet and Cancer Study: representativity, cancer incidence and mortality in participants and non-participants. Eur J Cancer Prev 2001; 10: 489–499.
19.
Almquist M, Bondeson AG, Bondeson L, Malm J, Manjer J: Serum levels of vitamin D, PTH and calcium and breast cancer risk-a prospective nested case-control study. Int J Cancer 2010; 127: 2159–2168.
20.
Brandstedt J, Almquist M, Manjer J, Malm J: Vitamin D, PTH, and calcium and the risk of prostate cancer: a prospective nested case-control study. Cancer Causes Control 2012; 23: 1377–1385.
21.
Enko D, Fridrich L, Rezanka E, Stolba R, Ernst J, Wendler I, Fabian D, Hauptlorenz S, Halwachs-Baumann G: 25-Hydroxy-vitamin D status: limitations in comparison and clinical interpretation of serum-levels across different assay methods. Clin Lab 2014; 60: 1541–1550.
22.
Traisk F, Tallstedt L, Abraham-Nordling M, Andersson T, Berg G, Calissendorff J, Hallengren B, Hedner P, Lantz M, Nystrom E, Ponjavic V, Taube A, Torring O, Wallin G, Asman P, Lundell G: Thyroid-associated ophthalmopathy after treatment for Graves’ hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab 2009; 94: 3700–3707.
23.
Nilsson PM, Nilsson JA, Berglund G: Population-attributable risk of coronary heart disease risk factors during long-term follow-up: the Malmö Preventive Project. J Intern Med 2006; 260: 134–141.
24.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
25.
Pantazi H, Papapetrou PD: Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism. J Clin Endocrinol Metab 2000; 85: 1099–1106.
26.
Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E: Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control 2004; 15: 255–265.
27.
Stefanic M, Karner I, Glavas-Obrovac L, Papic S, Vrdoljak D, Levak G, Krstonosic B: Association of vitamin D receptor gene polymorphism with susceptibility to Graves’ disease in Eastern Croatian population: case-control study. Croat Med J 2005; 46: 639–646.
28.
Ramos-Lopez E, Kurylowicz A, Bednarczuk T, Paunkovic J, Seidl C, Badenhoop K: Vitamin D receptor polymorphisms are associated with Graves’ disease in German and Polish but not in Serbian patients. Thyroid 2005; 15: 1125–1130.
29.
Ban Y, Taniyama M, Ban Y: Vitamin D receptor gene polymorphism is associated with Graves’ disease in the Japanese population. J Clin Endocrinol Metab 2000; 85: 4639–4643.
30.
Chen RH, Chang CT, Chen HY, Chen WC, Tsai CH, Tsai FJ: Association between vitamin-D receptor gene FokI polymorphism and Graves’ disease among Taiwanese Chinese. J Clin Lab Anal 2007; 21: 173–177.
31.
Collins JE, Heward JM, Nithiyananthan R, Nejentsev S, Todd JA, Franklyn JA, Gough SC: Lack of association of the vitamin D receptor gene with Graves’ disease in UK Caucasians. Clin Endocrinol 2004; 60: 618–624.
32.
Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D: Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 2010; 19: 2739–2745.
33.
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD: Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010; 376: 180–188.
34.
Arnaud J, Constans J: Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet 1993; 92: 183–188.
35.
Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, Nexo E: Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int 2005; 77: 15–22.
36.
Misharin A, Hewison M, Chen CR, Lagishetty V, Aliesky HA, Mizutori Y, Rapoport B, McLachlan SM: Vitamin D deficiency modulates Graves’ hyperthyroidism induced in BALB/c mice by thyrotropin receptor immunization. Endocrinology 2009; 150: 1051–1060.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.