Polymorphisms of FDPS, LRP5, SOST and VKORC1 genes and their relation with osteoporosis in postmenopausal Romanian women

Autoři: Alina Deniza Ciubean aff001;  Rodica Ana Ungur aff001;  Laszlo Irsay aff001;  Viorela Mihaela Ciortea aff001;  Ileana Monica Borda aff001;  Gabriela Bombonica Dogaru aff001;  Adrian Pavel Trifa aff002;  Stefan Cristian Vesa aff003;  Anca Dana Buzoianu aff003
Působiště autorů: Department of Rehabilitation, University of Medicine and Pharmacy “Iuliu Hațieganu”, Cluj-Napoca, Romania aff001;  Department of Genetics, University of Medicine and Pharmacy “Iuliu Hațieganu”, Cluj-Napoca, Romania aff002;  Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Medicine and Pharmacy “Iuliu Hațieganu”, Cluj-Napoca, Romania aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225776



This study aimed to assess the relationship between bone mineral density and genotypes of four polymorphisms in previously detected osteoporosis-candidate genes (FDPS rs2297480, LRP5 rs3736228, SOST rs1234612, VKORC1 rs9934438) in postmenopausal Romanian women with primary osteoporosis.


An analytical, prospective, transversal, observational, case-control study on 364 postmenopausal Romanian women was carried out between June 2016 and August 2017 in Cluj Napoca, Romania. Clinical data and blood samples were collected from all study participants. Four polymorphisms were genotyped using TaqMan SNP Genotyping assays, run on a QuantStudio 3 real-time PCR machine.


Women with TT genotype in FDPS rs2297480 had significantly lower bone mineral density values in the lumbar spine and total hip, and the presence of the T allele was significantly associated with the osteoporosis. Women carrying the CC genotype in LRP5 rs3736228 tend to have lower bone mineral density values in the femoral neck and total hip. No significant association was found for the genotypes of SOST rs1234612 or VKORC1 rs9934438.


Our study showed a strong association between bone mineral density and polymorphisms in the FDPS gene, and a borderline association with LRP5 and SOST polymorphisms in postmenopausal Romanian women with osteoporosis. No association was found for VKORC1.

Klíčová slova:

Alleles – Bone fracture – Hip – Molecular genetics – Osteoporosis – Romanian people – Variant genotypes


1. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761–1767. doi: 10.1016/S0140-6736(02)08657-9 12049882

2. Rivadeneira F, Mäkitie O. Osteoporosis and bone mass disorders: from gene pathways to treatments. Trends in Endocrinology & Metabolism. 2016 May 1;27(5):262–81.

3. Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev 2010;31:629–662. doi: 10.1210/er.2009-0044 20431112

4. Zofkova I, Nemcikova P, Kuklik M. Polymorphisms associated with low bone mass and high risk of atraumatic fracture. Physiological research 2015;64:621–631. 25804099

5. Rivadeneira F, Mäkitie O. Osteoporosis and bone mass disorders: from gene pathways to treatments. Trends in Endocrinology & Metabolism. 2016;27(5):262–81.

6. Angers S, Moon RT. Proximal events in Wnt signal transduction. Nature reviews Molecular cell biology. 2009;10(7):468. doi: 10.1038/nrm2717 19536106

7. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. The Lancet. 2008;371(9623):1505–12.

8. Levasseur R, Lacombe D, de Vernejoul MC. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint Bone Spine. 2005;72(3):207–14. doi: 10.1016/j.jbspin.2004.10.008 15850991

9. Golchin MM, Heidari L, Ghaderian SM, Akhavan-Niaki H. Osteoporosis: a silent disease with complex genetic contribution. Journal of Genetics and Genomics. 2016;43(2):49–61. doi: 10.1016/j.jgg.2015.12.001 26924688

10. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:6267–76. doi: 10.1093/emboj/cdg599 14633986

11. Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 2005;15:928–35 doi: 10.1101/gr.3437105 15965026

12. Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, et al. Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci USA. 2012;109:14092–7 doi: 10.1073/pnas.1207188109 22886088

13. Marozik P, Alekna V, Rudenko E, Tamulaitiene M, Rudenka A, Mastaviciute A, et al. Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis. PloS one. 2019;14(8).

14. Choi HJ, Choi JY, Cho SW, Kang D, Han KO, Kim SW, et al. Genetic polymorphism of geranylgeranyl diphosphate synthase (GGSP1) predicts bone density response to bisphosphonate therapy in Korean women. Yonsei medical journal. 2010;51(2):231–8. doi: 10.3349/ymj.2010.51.2.231 20191015

15. Wang C, Zheng H, He JW, Zhang H, Yue H, Hu WW, et al. Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. The pharmacogenomics journal. 2015;15(2):158. doi: 10.1038/tpj.2014.52 25223561

16. Han LW, Ma DD, Xu XJ, Lü F, Liu Y, Xia WB, et al. Association Between Geranylgeranyl Pyrophosphate Synthase Gene Polymorphisms and Bone Phenotypes and Response to Alendronate Treatment in Chinese Osteoporotic Women. Chinese Medical Sciences Journal. 2016;31(1):8–16. doi: 10.1016/s1001-9294(16)30016-5 28031082

17. Levy ME, Parker RA, Ferrell RE, Zmuda JM, Greenspan SL. Farnesyl diphosphate synthase: a novel genotype association with bone mineral density in elderly women. Maturitas 2007;57(3):247–252. doi: 10.1016/j.maturitas.2007.01.005 17368768

18. Marini F, Falchetti A, Silvestri S, Bagger Y, Luzi E, Tanini A, et al. Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis. Current Medical research and opinion. 2008;24(9):2609–15. doi: 10.1185/03007990802352894 18687167

19. Olmos JM, Zarrabeitia MT, Hernandez JL, Sanudo C, Gonzalez-Macias J, Riancho JA. Common allelic variants of the farnesyl diphosphate synthase gene influence the response of osteoporotic women to bisphosphonates. The pharmacogenomics journal 2012;12(3):227. doi: 10.1038/tpj.2010.88 21151198

20. Fodor D, Bondor C, Albu A, Popp R, Pop IV, Poanta L. Relationship between VKORC1 single nucleotide polymorphism 1173C> T, bone mineral density & carotid intima-media thickness. The Indian journal of medical research 2013;137(4):734. 23703341

21. Kutluturk F, Inanir A, Rustemoglu A, Kaya SU, Demir AK, Dursun G, et al. Association between Vitamin K Epoxide Reductase (VKORC1)-1639G> A Polymorphism and Osteoporosis in Postmenopausal Women. Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders). 2018;18(3):281–6.

22. Pop TR, Vesa ŞC, Trifa AP, Crişan S, Buzoianu AD. An acenocoumarol dose algorithm based on a South-Eastern European population. European journal of clinical pharmacology 2013;69(11):1901–1907. doi: 10.1007/s00228-013-1551-3 23774941

23. Marini F, Masi L, Marcucci G, Cianferotti L, Brandi ML. Genetics of Osteoporosis. In Multidisciplinary Approach to Osteoporosis. Cham: Springer;2018. p. 25–44

24. van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochemical and biophysical research communications 1999;264(1):108–111. doi: 10.1006/bbrc.1999.1499 10527849

25. Massart F, Marini F, Bianchi G, Minisola S, Luisetto G, Pirazzoli A, et al. Genetic predictors of skeletal outcomes in healthy fertile women: The Bonturno Study. Joint Bone Spine. 2013;80(4):414–9. doi: 10.1016/j.jbspin.2012.10.020 23238007

26. Harada SI, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003;423(6937):349. doi: 10.1038/nature01660 12748654

27. Canto‐Cetina T, Polanco Reyes L, González Herrera L, Rojano‐Mejía D, Coral‐Vázquez RM, Coronel A, et al. Polymorphism of LRP5, but not of TNFRSF11B, is associated with a decrease in bone mineral density in postmenopausal maya‐mestizo women. American Journal of Human Biology. 2013;25(6):713–8. doi: 10.1002/ajhb.22464 24130145

28. Mencej-Bedrač S, Preželj J, Kocjan T, Komadina R, Marc J. Analysis of association of LRP5, LRP6, SOST, DKK1, and CTNNB1 genes with bone mineral density in a Slovenian population. Calcified tissue international 2009;85(6):501–506. doi: 10.1007/s00223-009-9306-y 19898734

29. Falcón-Ramírez E, Casas-Avila L, Cerda-Flores RM, Castro-Hernández C, Rubio-Lightbourn J, Velázquez-Cruz R, et al. Association of LRP5 haplotypes with osteoporosis in Mexican women. Molecular biology reports. 2013;40(3):2705–10. doi: 10.1007/s11033-012-2357-6 23242660

30. Zhou PR, Liu HJ, Liao EY, Zhang ZL, Chen DC, Liu J, et al. LRP5 polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis. Pharmacogenomics. 2014;15(6):821–31. doi: 10.2217/pgs.14.12 24897288

31. Markatseli AE, Hatzi E, Bouba I, Georgiou I, Challa A, Tigas S, et al. Association of the A1330V and V667M polymorphisms of LRP5 with bone mineral density in Greek peri-and postmenopausal women. Maturitas. 2011;70(2):188–93. doi: 10.1016/j.maturitas.2011.07.016 21840657

32. Ezura Y, Nakajima T, Urano T, Sudo Y, Kajita M, Yoshida H, et al. Association of a single-nucleotide variation (A1330V) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density in adult Japanese women. Bone. 2007;40(4):997–1005. doi: 10.1016/j.bone.2005.06.025 17306638

33. Martínez-Gil N, Roca-Ayats N, Monistrol-Mula A, García-Giralt N, Díez-Pérez A, Nogués X, et al. Common and rare variants of WNT16, DKK1 and SOST and their relationship with bone mineral density. Scientific reports. 2018;8(1):10951. doi: 10.1038/s41598-018-29242-8 30026596

34. Uitterlinden AG, Arp PP, Paeper BW, Charmley P, Proll S, Rivadeneira F, et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. The American Journal of Human Genetics. 2004;75(6):1032–45. doi: 10.1086/426458 15514891

35. Valero C, Zarrabeitia MT, Hernández JL, Pineda B, Cano A, García-Pérez MA, et al. Relationship of sclerostin and secreted frizzled protein polymorphisms with bone mineral density: an association study with replication in postmenopausal women. Menopause. 2011;18(7):802–7. doi: 10.1097/gme.0b013e3182091664 21441835

36. Zhou PR, Xu XJ, Zhang ZL, Liao EY, Chen DC, Liu J, et al. SOST polymorphisms and response to alendronate treatment in postmenopausal Chinese women with osteoporosis. Pharmacogenomics. 2015;16(10):1077–88. doi: 10.2217/pgs.15.76 26250343

37. He J, Zhang H, Wang C, Zhang Z, Yue H, Hu W, et al. Associations of serum sclerostin and polymorphisms in the SOST gene with bone mineral density and markers of bone metabolism in postmenopausal Chinese women. The Journal of Clinical Endocrinology & Metabolism. 2014;99(4):E665–73.

38. Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, et al. Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Bone. 2002;31(4):515–9. doi: 10.1016/s8756-3282(02)00844-x 12398949

39. Velázquez-Cruz R, Jiménez-Ortega RF, Parra-Torres AY, Castillejos-López M, Patiño N, Quiterio M, et al. Analysis of association of MEF2C, SOST and JAG1 genes with bone mineral density in Mexican-Mestizo postmenopausal women. BMC musculoskeletal disorders. 2014;15(1):400.

40. Zhang H, He JW, Wang C, Zhang Z, Yue H, Hu WW, et al. Associations of polymorphisms in the SOST gene and bone mineral density in postmenopausal Chinese Women. Osteoporosis International. 2014;25(12):2797–803. doi: 10.1007/s00198-014-2832-0 25103216

41. Palermo A, Tuccinardi D, D’Onofrio L, Watanabe M, Maggi D, Maurizi AR, et al. Vitamin K and osteoporosis: Myth or reality?. Metabolism. 2017;70:57–71. doi: 10.1016/j.metabol.2017.01.032 28403946

42. Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald LF, Findlay DM. Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by γ-carboxylation-dependent and-independent mechanisms. American Journal of Physiology-Cell Physiology 2009;297(6):C1358–1367. doi: 10.1152/ajpcell.00216.2009 19675304

43. Crawford DC, Brown-Gentry K, Rieder MJ. VKORC1 common variation and bone mineral density in the Third National Health and Nutrition Examination Survey. PLoS One 2010;5(12):e15088. doi: 10.1371/journal.pone.0015088 21179439

44. Holzer G, Grasse AV, Zehetmayer S, Bencur P, Bieglmayer C, Mannhalter C. Vitamin K epoxide reductase (VKORC1) gene mutations in osteoporosis: A pilot study. Translational Research 2010;156(1):37–44. doi: 10.1016/j.trsl.2010.05.005 20621035

45. Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Archives of osteoporosis. 2013;8(1–2):136.

Článek vyšel v časopise


2019 Číslo 11