Relevance of CYP2R1 genetic polymorphism and individual therapy

doi:10.12092/j.issn.1009-2501.2019.09.014

Abstract

Abstract:

CYP2R1 is a member of the cytochrome P450 family 2 subfamily. As a 25-hydroxylase of vitamin D, it is responsible for the hydroxylation of vitamin D to 25-hydroxyvitamin D (25-OH-D), affecting the production of active hormone 1,25(OH)2D. The CYP2R1 mutation triggers a vitamin D-dependent rickets type 1B. The polymorphism of CYP2R1 is significantly correlated with the level of 25-OH-D, especially rs10741657. The CYP2R1 gene polymorphism affects its protein expression level and enzyme activity, and has a significant impact on the metabolic processes that it catalyzes. CYP2R1 regulates the immune response by regulating gene function and affects the risk of type 1 diabetes. Its polymorphism is associated with a variety of cancer risks, including breast cancer, prostate cancer, and colorectal cancer. Studying the CYP2R1 gene polymorphism is helpful for understanding the role of metabolic pathway changes in the development of related diseases, deepening the understanding of diseases such as cancer, rickets and type 1 diabetes, and promoting the detection and assessment of the risk of related diseases from the genetic level. This article reviews the research progress of metabolic pathways and gene polymorphisms involved in CYP2R1 in recent five years.

Key words: CYP2R1, genetic polymorphism, vitamin D deficiency, type 1diabetes, cancer

CLC Number:

R966
R587.1

LI Ling, ZHAO Huijia, CHEN Binyao, LIU Xiaohong, SUN Gongpeng, HAO Zhuowen, FAN Zhipeng, YUE Jiang, WU Jianguo, YE Qifa. Relevance of CYP2R1 genetic polymorphism and individual therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(9): 1053-1059.

References

［1］Nelson DR. Comparison of P450s from human and fugu: 420 million years of vertebrate P450 evolution［J］. Arch Biochem Biophys, 2003,409(1):18-24.
［2］Cheng JB, Motola DL, Mangelsdorf DJ, et al. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase［J］. J Biol Chem, 2003, 278(39):38084-38093.
［3］Rochel N,Molnár F.Structural aspects of vitamin D endocrinology［J］.Mol Cell Endocrinol,2017,453:22-35.
［4］Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study［J］. Lancet, 2010, 376(9736):180-188.
［5］Zhu JG, Ochalek JT, Kaufmann M, et al. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo［J］. Proc Natl Acad Sci U S A, 2013, 110(39):15650-15655.
［6］Al Mutair AN,Nasrat GH,Russell DW.Mutation of the CYP2R1 vitamin D 25hydroxylase in a Saudi Arabian family with severe vitamin D deficiency［J］.J Clin Endocrinol Metab,2012,97(10):E2022- E2025.
［7］Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D［J］. J Lipid Res, 2014, 55(1):13-31.
［8］Wjst M, Altmüller J, Faus-Kessler T, et al. Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway［J］. Respir Res,2006, 7:60.
［9］Wang Y, Yu F, Yu S, et al. Triangular relationship between CYP2R1 gene polymorphism, serum 25(OH)D3 levels and T2DM in a Chinese rural population［J］. Gene, 2018 , 3(18):30863-30871.
［10］Duan L,Xue Z,Ji H,et al.Effects of CYP2R1 gene variants on vitamin D levels and status: A systematic review and meta-analysis［J］.Gene,2018,678:361-369.
［11］Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on prevention and management of nutritional rickets［J］. J Clin Endocrinol Metab,2016,101(2):394-415.
［12］Spiro A, Buttriss JL. Vitamin D: An overview of vitamin D status and intake in Europe［J］. Nutr Bull, 2014,39(4):322-350.
［13］Casella SJ, Reiner BJ, Chen TC, et al. A possible genetic defectin 25-hydroxylation as a cause of rickets［J］. J Pediatr, 1994, 124(6):929-932.
［14］Thacher TD, Fischer PR, Singh RJ, et al. CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency［J］. J Clin Endocrinol Metab, 2015,100(7): E1005- E1013.
［15］Thacher TD, Levine MA. CYP2R1 mutations causing vitamin D-deficiency rickets［J］. J Steroid Biochem Mol Biol, 2017,173: 333-336.
［16］Xu X, Mao J, Zhang M, et al. Vitamin D deficiency in Uygurs and Kazaks is associated with polymorphisms in CYP2R1 and DHCR7/NADSYN1 genes［J］. Med Sci Monit, 2015,21: 1960-1968.
［17］Robert S, Korf H, Gysemans C, et al. Antigen-based vs. systemic immunomodulation in type 1 diabetes: the pros and cons［J］. Islets, 2013,5(2):53-66.
［18］Cantorna MT, Snyder L, Lin YD, et al. Vitamin D and 1,25(OH)2D regulation of T cells［J］. Nutrients, 2015, 7(4):3011-3021.
［19］Mazanova A, Shymanskyi I, Lisakovska O, et al. Effects of cholecalciferol on key components of vitamin D-endo/para/autocrine system in experimental type 1 diabetes［J］. Int J Endocrinol, 2018: 2494016.
［20］Morán-Auth Y,Penna-Martinez M,Shoghi F,et al.Vitamin D status and gene transcription in immune cells［J］.J Steroid Biochem Mol Biol,2013,136:83-85.
［21］Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children［J］. Cell Immunol,2012,279(1):42-45.
［22］Peng X, Shang G, Wang W, et al. Fatty acid oxidation in zebrafish adipose tissue is promoted by 1a,25(OH)2D3［J］. Cell Rep, 2017,19(7):1444-1455.
［23］Borges CC, Salles AF, Bringhenti I, et al. Vitamin D deficiency increases lipogenesis and reduces beta-oxidation in the liver of diet-induced obese mice［J］. J Nutr Sci Vitaminol (Tokyo), 2018,64(2):106-115.
［24］Soininen S, Eloranta AM, Viitasalo A, et al. Serum 25-Hydroxyvitamin D, plasma Lipids, and associated gene variants in prepubertal children［J］. J Clin Endocrinol Metab,2018, 103(7):2670-2679.
［25］Karonova T, Belyaeva O, Jude EB, et al. Serum 25(OH)D and adipokines levels in people with abdominal obesity［J］. J Steroid Biochem Mol Biol, 2018,75: 170-176.
［26］Tosunbayraktar G, Bas M, Kut A, et al. Low serum 25(OH)D levels are assocrated to higher BMI and metabolic syndrome parameters in adult subjects in Turkey［J］. Afr Health Sci,2015,15(4):1161-1169.
［27］Qi Q, Zheng Y, Huang T, et al. Vitamin D metabolism-related genetic variants, dietary protein intake and improvement of insulin resistance in a 2 years weight-loss trial: POUNDS lost ［J］. Diabetologia, 2015, 58(12):2791-2799.
［28］Christakos S, Dhawan P, Verstuyf A, et al. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects［J］. Physiol Rev, 2016, 96(1):365-408.
［29］Grant WB. A review of the evidence supporting the vitamin D-cancer prevention hypothesis in 2017［J］. Anticancer Res, 2018, 38(2):1121-1136.
［30］Moukayed M, Grant WB. The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: A review of the epidemiology, clinical trials, and mechanisms［J］. Rev Endocr Metab Disord, 2017, 18(2):167-182.
［31］Jeon SM, Shin EA. Exploring vitamin D metabolism and function in cancer［J］. Exp Mol Med, 2018 , 50(4):20.
［32］Urbschat A, Paulus P, von Quernheim QF, et al. Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell carcinoma［J］. Eur J Clin Invest, 2013,43(12):1282-1290.
［33］Estébanez N, Gómez-Acebo I, Palazuelos C, et al. Vitamin D exposure and Risk of Breast Cancer: a meta-analysis［J］. Sci Rep, 2018, 8(1):9039.
［34］Yao S, Kwan ML, Ergas IJ, et al. Association of serum level of vitamin D at diagnosis with breast cancer survival: a case-cohort analysis in the pathways Study［J］. JAMA Oncol, 2017, 3(3):351-357.
［35］Ratnadiwakara M, Williams RB, Blackburn AC. Abstract A117: Vitamin D, parathyroid hormone, Cyp2R1, and breast cancer susceptibility in mice［J］. Mol Cancer Res, 2013, 11(10): A117.
［36］Sheng L, Callen DF, Turner AG. Vitamin D3 signaling and breast cancer: Insights from transgenic mouse models［J］. J Steroid Biochem Mol Biol,2018,178: 348-353.
［37］O'Brien KM, Sandler DP, Kinyamu HK, et al. Single nucleotide polymorphisms in vitamin D-related genes may modify vitamin D-breast cancer associations［J］. Cancer Epidemiol Biomarkers Prev, 2017 , 26(12):1761-1771.
［38］Pibiri F, Kittles RA, Sandler RS, et al. Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans［J］. Cancer Causes Control, 2014,25(5):561-570.
［39］Szkandera J, Absenger G, Pichler M, et al. Association of common gene variants in vitamin D modulating genes and colon cancer recurrence［J］. J Cancer Res Clin Oncol, 2013,139(9):1457-1464.
［40］Ekmekcioglu C, Haluza D, Kundi M. 25-Hydroxyvitamin D status and risk for colorectal cancer and type 2 diabetes mellitus: A systematic review and meta-analysis of epidemiological studies［J］. Int J Environ Res Public Health, 2017,14(2) :pii: E127.
［41］Maalmi H, Walter V, Jansen L, et al. Relationship of very low serum 25-hydroxyvitamin D3 levels with long-term survival in a large cohort of colorectal cancer patients from Germany［J］. Eur J Epidemiol, 2017, 32(11):961-971.
［42］Dou R, Ng K, Giovannucci EL, et al. Giovannucci vitamin D and colorectal cancer: Molecular, epidemiological, and clinical evidence［J］. Br J Nutr, 2016 ,115(9):1643-1660.
［43］Morales-Oyarvide V, Meyerhardt JA, Ng K. Vitamin D and physical activity in patients with colorectal cancer: Epidemiological evidence and therapeutic implications［J］. Cancer J, 2016, 22(3):223-231.
［44］Anderson LN, Cotterchio M, Knight JA, et a. Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada［J］. PLoS One, 2013, 8(6): e66768.
［45］Meyer HE, Stoer NC, Samuelsen SO, et al. Long term association between serum 25-hydroxyvitamin D and mortality in a cohort of 4379 men［J］. PLoS One, 2016, 11(3): e0151441.
［46］Gao J, Wei W, Wang G, et al. Circulating vitamin D concentration and risk of prostate cancer: a dose-response meta-analysis of prospective studies［J］. Ther Clin Risk Manag, 2018 , 14: 95-104.
［47］Tak YJ, Lee JG, Kim YJ, et al. Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study［J］. Asian J Androl, 2015, 17(2):324-328.

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