vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2020-17-4-480-492vestim-717Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEСвязь полиморфизма гена рецептора витамина D с показателями минеральной плотности костной ткани и уровнем 25(OH)D у женщин с остеопорозомVitamin D receptor gene polymorphism, bone mineral density and 25(OH)D level in women with оsteopоrosisРуденкоЕ. В.RudenkaA. V.

Руденко Елена Викторовна – кандидат медицинских наук, доцент

ул. П. Бровки, 3/3, 220013, г. Минск

Alena V. Rudenka – Ph. D. (Med.), Assistant Professor

3/3, P. Browka Str., 220013, Minsk

alenka.v.ru@gmail.comРуденкоЭ. В.RudenkaE. V.

Руденко Эмма Владимировна – доктор медицинских наук, профессор

пр. Дзержинского, 83, 220116, г. Минск

Ema V. Rudenka – D. Sc. (Med.), Professor

83, Dzerzhinski Ave., 220116, Minsk

rudenka.ema@gmail.comСамоховецО. Ю.SamokhovecV. Yu.

Самоховец Ольга Юрьевна – кандидат медицинских наук, врач

пр. Независимости, 64, 220013, г. Минск

Volha Yu. Samokhovec – Ph. D. (Med.), Doctor

64, Nezavisimosti Ave., 22013, Minsk

samokhovec.olga@gmail.comКобецЕ. В.KobetsK. V.

Кобец Екатерина Вячеславовна – науч. сотрудник

ул. Академическая, 27, 220072, г. Минск

Katsiaryna V. Kobets – Researcher

27, Akademicheskaya Str., 220072, Minsk

E.Kobets@igc.byМорозикП. М.MarozikP. M.

Морозик Павел Михайлович – кандидат биологических наук, доцент, заведующий лабораторией

ул. Академическая, 27, 220072, г. Минск

Pavel M. Marozik – Ph. D. (Biol.), Assistant Professor, Head of the Laboratory

27, Akademicheskaya Str., 220072, Minsk

P.Marozik@igc.byБелорусская медицинская академия последипломного образованияBelarusian Medical Academy of Postgraduate EducationБелорусский государственный медицинский университетBelarusian State Medical UniversityГородской центр профилактики остеопороза и болезней костно-мышечной системыCity Center for Osteoporosis and Bone-Muscular Diseases PreventionИнститут генетики и цитологии НАН БеларусиInstitute of Genetics and Cytology of the National Academy of Sciences of Belarus202005122020174480492Copyright © Руденко Е.В., Руденко Э.В., Самоховец О.Ю., Кобец Е.В., Морозик П.М., 20202020Руденко Е.В., Руденко Э.В., Самоховец О.Ю., Кобец Е.В., Морозик П.М.Rudenka A.V., Rudenka E.V., Samokhovec V.Y., Kobets K.V., Marozik P.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/717

Витамин D является секостероидным гормоном, который реализует свои многочисленные клеточные эффекты, инициируя транскрипцию витамин D-зависимых генов. Несмотря на большое количество проведенных исследований, точная роль вариантов гена VDR с уровнем минеральной плотности костей (МПК) и риском остеопороза (OП) до сих пор не установлена. Разработка и внедрение методики прогнозирования индивидуального риска ОП и/или костных переломов на основании генетического тестирования имеет большое значение для своевременной профилактики заболевания. Целью настоящего исследования являлась разработка прогностической модели оценки индивидуального риска развития ОП у женщин Беларуси, включающей анализ полиморфных вариантов гена VDR. В исследование были включены женщины в постменопаузе с ОП (n = 350), контрольную группу составили женщины с нормальной МПК, без низкотравматических переломов (n = 243). Генотипирование вариантов ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570 и Cdx2 rs11568820 гена VDR осуществляли методом ПЦР с использованием проб TaqMan. По результатам исследования была выявлена значимая ассоциация генотипов ApaI A/A (p  =  0,045), BsmI T/T (p = 0,015) и TaqI G/G (p = 0,005), а также их гаплотипа A-T-G (OR = 4,6; p = 0,003) с повышенным риском ОП. Эти же варианты, а также Cdx2 rs11568820 коррелировали с уровнем МПК (p <0,05 во всех случаях). Показано, что среди носителей неблагоприятных аллелей исследованных вариантов гена VDR уровень 25(OH)D в сыворотке был существенно повышен (β = 4,1; p = 0,007). Построенная из информативных вариантов гена VDR модель оценки индивидуального риска ОП имела хорошую прогностическую ценность (AUC = 0,79) с высоким уровнем чувствительности (82,9 %) и средней специфичностью (69,4 %). Полученные нами результаты подчеркивают важность проанализированных вариантов гена VDR для прогнозирования индивидуального риска ОП.

Vitamin D plays an important role in bone metabolism and pathology. Although the VDR gene is one of the most studied determinants of bone mineral density (BMD) and osteoporosis (OP), its exact effects have yet to be established. Prediction of OP and/or fracture risk, based on individual genetic profile, is of high importance. The aim of our study was to develop prognostic model for postmenopausal OP individual risk evaluation in Belarusian women, based on the analysis of VDR gene variants. Case group included women with postmenopausal OP (n = 350), the control group comprised of women with normal BMD and without previous fragility fractures (n  =  243). VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570 and Cdx2 rs11568820 variants were determined using TaqMan genotyping assays. We revealed a significant association of single ApaI A/A (p = 0.045), BsmI T/T (p = 0.015) and TaqI G/G (p = 0.005) variants and their A-T-G-haplotype (OR  =  4.6, p  =  0.003) with increased OP risk. Together with Cdx2 rs11568820, these variants correlated with BMD (p <0.05 in all cases). For the bearers of non-favorable alleles of VDR gene variants, the serum 25(OH)D level was significantly increased. The constructed from informative VDR gene variants model of individual OP risk evaluation possessed a good prognostic value (AUC = 0.79) with high sensitivity level (82.9 %) and average specificity (69.4 %). Our findings highlight the importance of analyzed VDR gene variants for personalized OP risk prediction.

витамин Dгенетический рискпрогнозирующая модельварианты генагаплотиппостменопаузальный остеопорозvitamin Dgenetic riskpredictive modelgene variantshaplotypepostmenopausal osteoporosisReferencesChristakos S., Dhawan P., Verstuyf A., Verlinden L., Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiological Reviews, 2016, vol. 96, no. 1, pp. 365–408. https://doi.org/10.1152/physrev.00014.2015Christakos S., Dhawan P., Verstuyf A., Verlinden L., Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiological Reviews, 2016, vol. 96, no. 1, pp. 365–408. https://doi.org/10.1152/physrev.00014.2015Pludowski P., Holick M. F., Pilz S., Wagner C. L., Hollis B. W., Grant W. B. [et al.]. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality – a review of recent evidence. Autoimmunity Reviews, 2013, vol. 12, no. 10, pp. 976–989. https://doi.org/10.1016/j.autrev.2013.02.004Pludowski P., Holick M. F., Pilz S., Wagner C. L., Hollis B. W., Grant W. B. [et al.]. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality – a review of recent evidence. Autoimmunity Reviews, 2013, vol. 12, no. 10, pp. 976–989. https://doi.org/10.1016/j.autrev.2013.02.004Miyamoto K., Kesterson R. A., Yamamoto H., Taketani Y., Nishiwaki E., Tatsumi S., Inoue Y., Morita K., Takeda E., Pike J. W. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Molecular Endocrinology, 1997, vol. 11, no. 8, pp. 1165–1179. https://doi.org/10.1210/mend.11.8.9951Miyamoto K., Kesterson R. A., Yamamoto H., Taketani Y., Nishiwaki E., Tatsumi S., Inoue Y., Morita K., Takeda E., Pike J. W. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Molecular Endocrinology, 1997, vol. 11, no. 8, pp. 1165–1179. https://doi.org/10.1210/mend.11.8.9951Yamamoto H., Miyamoto K., Li B., Taketani Y., Kitano M., Inoue Y., Morita K., Pike J. W., Takeda E. The caudalrelated homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. Journal of Bone and Mineral Research, 1999, vol. 14, no. 2, pp. 240–247. https://doi.org/10.1359/jbmr.1999.14.2.240Yamamoto H., Miyamoto K., Li B., Taketani Y., Kitano M., Inoue Y., Morita K., Pike J. W., Takeda E. The caudalrelated homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. Journal of Bone and Mineral Research, 1999, vol. 14, no. 2, pp. 240–247. https://doi.org/10.1359/jbmr.1999.14.2.240Arai H., Miyamoto K. I., Yoshida M., Yamamoto H., Taketani Y., Morita K. [et al.]. The polymorphism in the caudalrelated homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. Journal of Bone and Mineral Research, 2001, vol. 16, no. 7, pp. 1256–1264. https://doi.org/10.1359/jbmr.2001.16.7.1256Arai H., Miyamoto K. I., Yoshida M., Yamamoto H., Taketani Y., Morita K. [et al.]. The polymorphism in the caudalrelated homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. Journal of Bone and Mineral Research, 2001, vol. 16, no. 7, pp. 1256–1264. https://doi.org/10.1359/jbmr.2001.16.7.1256Gross C., Krishnan A. V., Malloy P. J., Eccleshall T. R., Zhao X. Y., Feldman D. The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. Journal of Bone and Mineral Research, 1998, vol. 13, no. 11, pp. 1691–1699. https://doi.org/10.1359/jbmr.1998.13.11.1691Gross C., Krishnan A. V., Malloy P. J., Eccleshall T. R., Zhao X. Y., Feldman D. The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. Journal of Bone and Mineral Research, 1998, vol. 13, no. 11, pp. 1691–1699. https://doi.org/10.1359/jbmr.1998.13.11.1691Zhang L., Yin X., Wang J., Xu D., Wang Y., Yang J., Tao Y., Zhang S., Feng X., Yan C. Associations between VDR gene polymorphisms and osteoporosis risk and bone mineral density in postmenopausal women: a systematic review and metaanalysis. Scientific Reports, 2018, vol. 8, no. 1, p. 981. https://doi.org/10.1038/s41598-017-18670-7Zhang L., Yin X., Wang J., Xu D., Wang Y., Yang J., Tao Y., Zhang S., Feng X., Yan C. Associations between VDR gene polymorphisms and osteoporosis risk and bone mineral density in postmenopausal women: a systematic review and metaanalysis. Scientific Reports, 2018, vol. 8, no. 1, p. 981. https://doi.org/10.1038/s41598-017-18670-7Jurutka P. W., Whitfield G. K., Hsieh J. C., Thompson P. D., Haussler C. A., Haussler M. R. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Reviews in Endocrine and Metabolic Disorders, 2001, vol. 2, no. 2, pp. 203–216. https://doi.org/10.1023/a:1010062929140Jurutka P. W., Whitfield G. K., Hsieh J. C., Thompson P. D., Haussler C. A., Haussler M. R. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Reviews in Endocrine and Metabolic Disorders, 2001, vol. 2, no. 2, pp. 203–216. https://doi.org/10.1023/a:1010062929140Uitterlinden A. G., Weel A. E., Burger H., Fang Y., van Duijn C. M., Hofman A., van Leeuwen J. P., Pols H. A. Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture. Journal of Bone and Mineral Research, 2001, vol. 16, no. 2, pp. 379–385. https://doi.org/10.1359/jbmr.2001.16.2.379Uitterlinden A. G., Weel A. E., Burger H., Fang Y., van Duijn C. M., Hofman A., van Leeuwen J. P., Pols H. A. Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture. Journal of Bone and Mineral Research, 2001, vol. 16, no. 2, pp. 379–385. https://doi.org/10.1359/jbmr.2001.16.2.379Horst-Sikorska W., Kalak R., Wawrzyniak A., Marcinkowska M., Celczynska-Bajew L., Slomski R. Association analysis of the polymorphisms of the VDR gene with bone mineral density and the occurrence of fractures. Journal of Bone and Mineral Metabolism, 2007, vol. 25, no. 5, pp. 310–319. doi:10.1007/s00774-007-0769-5Horst-Sikorska W., Kalak R., Wawrzyniak A., Marcinkowska M., Celczynska-Bajew L., Slomski R. Association analysis of the polymorphisms of the VDR gene with bone mineral density and the occurrence of fractures. Journal of Bone and Mineral Metabolism, 2007, vol. 25, no. 5, pp. 310–319. doi:10.1007/s00774-007-0769-5Zintzaras E., Rodopoulou P., Koukoulis G. N. BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Disease Markers, 2006, vol. 22, no. 5–6, pp. 317–326. https://doi.org/10.1155/2006/921694Zintzaras E., Rodopoulou P., Koukoulis G. N. BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Disease Markers, 2006, vol. 22, no. 5–6, pp. 317–326. https://doi.org/10.1155/2006/921694Marozik P., Mosse I., Alekna V., Rudenko E., Tamulaitienė M., Ramanau H. [et al.]. Association between polymorphisms of VDR, COL1A1, and LCT genes and bone mineral density in Belarusian women with severe postmenopausal osteoporosis. Medicina (Kaunas), 2013, vol. 49, no. 4, pp. 177–184.Marozik P., Mosse I., Alekna V., Rudenko E., Tamulaitienė M., Ramanau H. [et al.]. Association between polymorphisms of VDR, COL1A1, and LCT genes and bone mineral density in Belarusian women with severe postmenopausal osteoporosis. Medicina (Kaunas), 2013, vol. 49, no. 4, pp. 177–184.Pedrera-Canal M., Moran J. M., Vera V., Roncero-Martin R., Lavado-Garcia J. M., Aliaga I., Pedrera-Zamorano J. D. Lack of influence of vitamin D receptor BsmI (rs1544410) polymorphism on the rate of bone loss in a cohort of postmenopausal spanish women affected by osteoporosis and followed for five years. PLoS ONE, 2015, vol. 10, no. 9, p. e0138606. https://doi.org/10.1371/journal.pone.0138606Pedrera-Canal M., Moran J. M., Vera V., Roncero-Martin R., Lavado-Garcia J. M., Aliaga I., Pedrera-Zamorano J. D. Lack of influence of vitamin D receptor BsmI (rs1544410) polymorphism on the rate of bone loss in a cohort of postmenopausal spanish women affected by osteoporosis and followed for five years. PLoS ONE, 2015, vol. 10, no. 9, p. e0138606. https://doi.org/10.1371/journal.pone.0138606Colombini A., Brayda-Bruno M., Lombardi G., Croiset S. J., Ceriani C., Buligan C., Barbina M., Banfi G., Cauci S. BsmI, ApaI and TaqI Polymorphisms in the vitamin D receptor gene (VDR) and association with lumbar spine pathologies: an Italian case-control study. PLoS ONE, 2016, vol. 11, no. 5, p. e0155004. https://doi.org/10.1371/journal.pone.0155004Colombini A., Brayda-Bruno M., Lombardi G., Croiset S. J., Ceriani C., Buligan C., Barbina M., Banfi G., Cauci S. BsmI, ApaI and TaqI Polymorphisms in the vitamin D receptor gene (VDR) and association with lumbar spine pathologies: an Italian case-control study. PLoS ONE, 2016, vol. 11, no. 5, p. e0155004. https://doi.org/10.1371/journal.pone.0155004Zhao B., Zhang W., Du S., Zhou Z. Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women. Archives of Medical Science, 2016, vol. 12, no. 1, pp. 25–30. https://doi.org/10.5114/aoms.2016.57475Zhao B., Zhang W., Du S., Zhou Z. Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women. Archives of Medical Science, 2016, vol. 12, no. 1, pp. 25–30. https://doi.org/10.5114/aoms.2016.57475Marozik P., Alekna V., Rudenko E., Tamulaitiene M., Rudenka A., Mastaviciute A., Samokhovec V., Cernovas A., Kobets K., Mosse I. Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis. PLoS ONE, 2019, vol. 14, no. 8, p. e0221511. https://doi.org/10.1371/journal.pone.0221511Marozik P., Alekna V., Rudenko E., Tamulaitiene M., Rudenka A., Mastaviciute A., Samokhovec V., Cernovas A., Kobets K., Mosse I. Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis. PLoS ONE, 2019, vol. 14, no. 8, p. e0221511. https://doi.org/10.1371/journal.pone.0221511Cosman F., de Beur S. J., LeBoff M. S., Lewiecki E. M., Tanner B., Randall S., Lindsay R.; National osteoporosis foundation. clinician’s guide to prevention and treatment of osteoporosis. Osteoporosis International, 2014, vol. 25, no. 10, pp. 2359–2381. https://doi.org/10.1007/s00198-014-2794-2Cosman F., de Beur S. J., LeBoff M. S., Lewiecki E. M., Tanner B., Randall S., Lindsay R.; National osteoporosis foundation. clinician’s guide to prevention and treatment of osteoporosis. Osteoporosis International, 2014, vol. 25, no. 10, pp. 2359–2381. https://doi.org/10.1007/s00198-014-2794-2Holick M. F., Binkley N. C., Bischoff-Ferrari H. A., Gordon C. M., Hanley D. A., Heaney R. P., Murad M. H., Weaver C. M. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Bone and Mineral Metabolism, 2011, vol. 96, no. 7, pp. 1911–1930. https://doi.org/10.1210/jc.2011-0385Holick M. F., Binkley N. C., Bischoff-Ferrari H. A., Gordon C. M., Hanley D. A., Heaney R. P., Murad M. H., Weaver C. M. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Bone and Mineral Metabolism, 2011, vol. 96, no. 7, pp. 1911–1930. https://doi.org/10.1210/jc.2011-0385Sempos C. T., Heijboer A. C., Bikle D. D., Bollerslev J., Bouillon R., Brannon P. M. [et al.]. Vitamin D assays and the definition of hypovitaminosis D: results from the First International conference on controversies in vitamin D. British Journal of Clinical Pharmacology, 2018, vol. 84, no. 10, pp. 2194–2207. https://doi.org/10.1111/bcp.13652Sempos C. T., Heijboer A. C., Bikle D. D., Bollerslev J., Bouillon R., Brannon P. M. [et al.]. Vitamin D assays and the definition of hypovitaminosis D: results from the First International conference on controversies in vitamin D. British Journal of Clinical Pharmacology, 2018, vol. 84, no. 10, pp. 2194–2207. https://doi.org/10.1111/bcp.13652Pilz S., Zittermann A., Trummer C., Theiler-Schwetz V., Lerchbaum E., Keppel M. H., Grübler M. R., März W., Pandis M. Vitamin D testing and treatment: a narrative review of current evidence. Endocrine Connections, 2019, vol. 8, no. 2, pp. R27–R43. https://doi.org/10.1530/EC-18-0432Pilz S., Zittermann A., Trummer C., Theiler-Schwetz V., Lerchbaum E., Keppel M. H., Grübler M. R., März W., Pandis M. Vitamin D testing and treatment: a narrative review of current evidence. Endocrine Connections, 2019, vol. 8, no. 2, pp. R27–R43. https://doi.org/10.1530/EC-18-0432Marozik P. M., Tamulaitiene M., Rudenka E., Alekna V., Mosse I., Rudenka A., Samokhovec V., Kobets K. Association of Vitamin D receptor gene variation with osteoporosis risk in belarusian and lithuanian postmenopausal women. Frontiers in Endocrinology (Lausanne), 2018, vol. 9, p. 305. https://doi.org/10.3389/fendo.2018.00305Marozik P. M., Tamulaitiene M., Rudenka E., Alekna V., Mosse I., Rudenka A., Samokhovec V., Kobets K. Association of Vitamin D receptor gene variation with osteoporosis risk in belarusian and lithuanian postmenopausal women. Frontiers in Endocrinology (Lausanne), 2018, vol. 9, p. 305. https://doi.org/10.3389/fendo.2018.00305Rudenko E. V., Rudenko E. V., Samokhovets O. Yu., Kobets E. V., Morozik P. M. Association of vitamin D receptor gene polymorphism with a bone mineral density level in postmenopausal women. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seriya meditsinskikh navuk = Proceeding of the National Academy of Sciences of Belarus. Medical series, 2019, vol. 16, no. 2, pp. 192–201 (in Russian). https://doi.org/10.29235/1814-6023-2019-16-2-192-201Rudenko E. V., Rudenko E. V., Samokhovets O. Yu., Kobets E. V., Morozik P. M. Association of vitamin D receptor gene polymorphism with a bone mineral density level in postmenopausal women. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seriya meditsinskikh navuk = Proceeding of the National Academy of Sciences of Belarus. Medical series, 2019, vol. 16, no. 2, pp. 192–201 (in Russian). https://doi.org/10.29235/1814-6023-2019-16-2-192-201Thakkinstian A., D’Este C., Attia J. Haplotype analysis of VDR gene polymorphisms: a meta-analysis. Osteoporosis International, 2004, vol. 15, no. 9, pp. 729–734. https://doi.org/10.1007/s00198-004-1601-xThakkinstian A., D’Este C., Attia J. Haplotype analysis of VDR gene polymorphisms: a meta-analysis. Osteoporosis International, 2004, vol. 15, no. 9, pp. 729–734. https://doi.org/10.1007/s00198-004-1601-xMorrison N. A., Qi J. C., Tokita A., Kelly P. J., Crofts L., Nguyen T. V., Sambrook P. N., Eisman J. A. Prediction of bone density from vitamin D receptor alleles. Nature, 1994, vol. 367, no. 6460, pp. 284–287. https://doi.org/10.1038/367284a0Morrison N. A., Qi J. C., Tokita A., Kelly P. J., Crofts L., Nguyen T. V., Sambrook P. N., Eisman J. A. Prediction of bone density from vitamin D receptor alleles. Nature, 1994, vol. 367, no. 6460, pp. 284–287. https://doi.org/10.1038/367284a0Luo X. Y., Yang M. H., Wu F. X., Wu L. J., Chen L., Tang Z., Liu N. T., Zeng X. F., Guan J. L., Yuan G. H. Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population. Lupus, 2012, vol. 21, no. 1, pp. 53–59. https://doi.org/10.1177/0961203311422709Luo X. Y., Yang M. H., Wu F. X., Wu L. J., Chen L., Tang Z., Liu N. T., Zeng X. F., Guan J. L., Yuan G. H. Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population. Lupus, 2012, vol. 21, no. 1, pp. 53–59. https://doi.org/10.1177/0961203311422709Fang Y., van Meurs J. B., d’Alesio A., Jhamai M., Zhao H., Rivadeneira F. [et al.]. Promoter and 3-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the Rotterdam study. American Journal of Human Genetics, 2005, vol. 77, no. 5, pp. 807–823. https://doi.org/10.1086/497438Fang Y., van Meurs J. B., d’Alesio A., Jhamai M., Zhao H., Rivadeneira F. [et al.]. Promoter and 3-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the Rotterdam study. American Journal of Human Genetics, 2005, vol. 77, no. 5, pp. 807–823. https://doi.org/10.1086/497438Monticielo O. A., Brenol J. C., Chies J. A., Longo M. G., Rucatti G. G., Scalco R., Xavier R. M. The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus, 2012, vol. 21, no. 1, pp. 43–52. https://doi.org/10.1177/0961203311421798Monticielo O. A., Brenol J. C., Chies J. A., Longo M. G., Rucatti G. G., Scalco R., Xavier R. M. The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus, 2012, vol. 21, no. 1, pp. 43–52. https://doi.org/10.1177/0961203311421798Al-Daghri N. M., Mohammed A. K., Al-Attas O. S., Ansari M. G. A., Wani K., Hussain S. D., Sabico S., Tripathi G., Alokail M. S. Vitamin D receptor gene polymorphisms modify cardiometabolic response to vitamin D supplementation in T2DM patients. Scientific Reports, 2017, vol. 7, no. 1, p. 8280. https://doi.org/10.1038/s41598-017-08621-7Al-Daghri N. M., Mohammed A. K., Al-Attas O. S., Ansari M. G. A., Wani K., Hussain S. D., Sabico S., Tripathi G., Alokail M. S. Vitamin D receptor gene polymorphisms modify cardiometabolic response to vitamin D supplementation in T2DM patients. Scientific Reports, 2017, vol. 7, no. 1, p. 8280. https://doi.org/10.1038/s41598-017-08621-7Gaffney-Stomberg E., Lutz L. J., Shcherbina A., Ricke D. O., Petrovick M., Cropper T. L., Cable S. J., McClung J. P. Association between single gene polymorphisms and bone biomarkers and response to calcium and vitamin D supplementation in young adults undergoing military training. Journal of Bone and Mineral Research, 2017, vol. 32, no. 3, pp. 498–507. https://doi.org/10.1002/jbmr.3008Gaffney-Stomberg E., Lutz L. J., Shcherbina A., Ricke D. O., Petrovick M., Cropper T. L., Cable S. J., McClung J. P. Association between single gene polymorphisms and bone biomarkers and response to calcium and vitamin D supplementation in young adults undergoing military training. Journal of Bone and Mineral Research, 2017, vol. 32, no. 3, pp. 498–507. https://doi.org/10.1002/jbmr.3008Pepe M. S., Janes H., Longton G., Leisenring W., Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. American Journal of Epidemiology, 2004, vol. 159, no. 9, pp. 882–890. https://doi.org/10.1093/aje/kwh101Pepe M. S., Janes H., Longton G., Leisenring W., Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. American Journal of Epidemiology, 2004, vol. 159, no. 9, pp. 882–890. https://doi.org/10.1093/aje/kwh101

The authors declare that there are no conflicts of interest present.