The relationship between some electrolyte levels and MTHFR C667T gene polymorphism in premenopausal and postmenopausal osteoporosis Iraqi women


Gene polymorphism related to osteoporosis plays a significant role in the development of osteoporosis, therefore, this study aimed to detect the MTHFR C667T gene polymorphism and evaluate its relationship with biochemical parameters in Iraqi women with premenopausal and postmenopausal osteoporosis in Salah Al-din province. Blood samples were collected from one hundred women (53 premenopausal and 47 postmenopausal) with osteoporosis diagnosed by specialist doctors and seventy healthy women with identical ages. Serum calcium and phosphorus concentrations were estimated and genomic DNA was extracted that used to detected MTHFR C667T polymorphism employing Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) technique. The results showed a significant decrease in the calcium and phosphorus concentrations (p-value <0.001) for the osteoporosis group compared with controls. Frequency of T allele and TT genotype were high significant (p-value < 0.001) in osteoporosis patients compared with controls. But there were no significant differences in the frequency of genotypes and alleles between patients group. On the other hand, there was no correlation between the decrease of calcium and phosphorus levels and presence of T allele in the genotypes of patients (p-value > 0.05). Conclude that calcium and phosphorus levels and frequency of normal CC genotype were decreased while the frequency of mutant TT genotype was higher in women with osteoporosis compared to healthy women, this indicates that TT genotype and T allele can be considered as an indicator of osteoporosis in Iraqi women.


  • Abrahamsen BO, Madsen JS, Landbo Tofteng C, Stilgren L, Bladbjerg EM, Kristensen SR, Mosekilde L (2003) A common methylenetetrahydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish osteoporosis prevention study. Journal of Bone and Mineral Research 18(4): 723-729.‏
  • Ahn TK, Kim J, Kim H, Park H, Shim J, Ropper A, ... Kim N (2018) 3′-UTR Polymorphisms of MTHFR and TS Associated with Osteoporotic Vertebral Compression Fracture Susceptibility in Postmenopausal Women. International journal of molecular sciences 19(3): 824.‏
  • Al Anouti F, Taha Z, Shamim S, Khalaf K, Al Kaabi L, Alsafar H (2019) An insight into the paradigms of osteoporosis: From genetics to biomechanics. Bone reports, 100216.‏
  • Ali NK (2018) Estimation of some mineral (calcium, phosphorous, vitamin 25 (OH) D and alkaline phosphatase) in osteoporosis patients in Kirkuk city. J Osteopor Phys Act 6(2).‏
  • Allen MR, Burr DB (2014) Bone modeling and remodeling. In Basic and applied bone biology (pp. 75-90). Academic Press.‏
  • Almayahi BA, Alhusseini LB, Kadhim AS (2016) A Study of Some Immunological and Biochemical Indicators for Patients with Osteoporosis. Electronic J Biol 12(1).‏
  • Anastasilakis AD, Polyzos SA, Makras P (2018) Therapy of endocrine disease: denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. European journal of endocrinology 179(1): R31-R45.
  • Arnaud CD, Sanchez SD (1990) The role of calcium in osteoporosis. Annual Review of Nutrition. Annual Review of Nutrition 10: 397- 414.
  • Asoodeh S, Motlagh AT (2015) Investigating the Density Ratios of Geological Structure through Fractal Geometry Case Stady:(Dehno Region in Farss of Iran). International Journal of Geography and Geology, 4(2): 37-46.
  • AuerkariI EI, Kusdhany L, Umami SS, Rahardjo TBW, Talbot C (2017) Polymorphism of methylenetetrahydrofolate reductase (A1298C) as a risk factor for osteoporosis in post-menopausal Indonesian women. Asian J Pharm Clin Res 10(10): 172-175.‏
  • Berndt T, Kumar R (2009) Novel mechanisms in the regulation of phosphorus homeostasis. Physiology 24(1): 17-25.‏
  • Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins”and theregulation of phosphorus homeostasis. Am J Physiol Renal Physiol289: F1170–F1182
  • Brambila-Tapia AJL, Durán-González J, Sandoval-Ramírez L, Mena JP, Salazar-Páramo M, Gámez-Nava JI, ... del Mercado MV (2012) MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. Disease markers 32(2): 109-114.‏
  • Cauley JA (2011) Defining ethnic and racial differences in osteoporosis and fragility fractures. Clinical Orthopaedics and Related Research® 469(7): 1891.‏
  • Cohen A (2017) Premenopausal Osteoporosis. Endocrinology and metabolism clinics of North America 46(1): 117–133.
  • Deformity A, PLANTER-FLEXED DO (2018) EUROSPINE Meetings 2018. European Spine Journal 27(5): S625-S678.‏
  • Du Y, Zhao L, Xu Q, Deng H (2017) Osteoporosis Preventive Behaviors and Bone Mineral Density among Older White and Asian Women. Innovation in aging 1(suppl_1): 143-143.‏
  • Eroglu S, Karatas G, Aziz V, Gursoy AF, Ozel S, Gulerman HC (2019) Evaluation of bone mineral density and its associated factors in postpartum women. Taiwanese Journal of Obstetrics and Gynecology 58(6): 801-804.‏
  • Guan JZ, Wu M, Xiao YZ, Zhou JS, Wang ZD (2014) MTHFR C677T polymorphism and osteoporotic fracture in postmenopausal women: a meta-analysis. Genetics and molecular research: GMR 13(3): 7356-7364.‏
  • Hendrickx G, Boudin E, Van Hul W (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nature Reviews Rheumatology 11(8): 462.‏
  • Jeong J, Kim JH, Shim JH, Hwang NS, Heo CY (2019) Bioactive calcium phosphate materials and applications in bone regeneration. Biomaterials research 23(1): 4.‏
  • Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D (1997) Guidelines for diagnosis and management of osteoporosis. The European foundation for osteoporosis and bone disease. Osteoporosis Int 7: 390-406.
  • Li D, Wu J (2010) Association of the MTHFR C677T polymorphism and bone mineral density in postmenopausal women: a meta-analysis. Journal of biomedical research 24(6): 417-423.‏
  • Li GHY, Robinson-Cohen C, Sahni S, Au PCM, Tan KCB, Kung AWC, Cheung CL (2019) Association of Genetic Variants Related to Serum Calcium Levels with Reduced Bone Mineral Density. The Journal of Clinical Endocrinology & Metabolism.‏
  • Li HZ, Wang W, Liu YL, He XF (2016) Association between the methylenetetrahydrofolate reductase c. 677C> T polymorphism and bone mineral density: an updated meta-analysis. Molecular Genetics and Genomics 291(1): 169-180.‏
  • Liu X, Liu H, Xiong Y, Yang L, Wang C, Zhang R, Zhu X (2018) Postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. Biomedicine & Pharmacotherapy 104: 742-750.‏
  • Martínez-Morillo M, Grados D, Holgado S (2012) Premenopausal osteoporosis: how to treat?. Reumatología Clínica (English Edition) 8(2): 93-97.‏
  • Martins JS, Palhares MDO, Teixeira OCM, Gontijo Ramos M (2017) Vitamin D status and its association with parathyroid hormone concentration in Brazilians. Journal of nutrition and metabolism.
  • Meier L, van SERSOOSKERKEN AMVT, Liberton E, Kleijn L, Westgeest T, Polak M (2010) Fractures of the proximal tibia associated with longterm use of methotrexate: 3 case reports and a review of literature. The Journal of rheumatology 37(11): 2434-2438.
  • Mutlu M, Argun M, Kilic E, Saraymen R, Yazar S (2007) Magnesium, zinc and copper status in osteoporotic, osteopenic and normal post-menopausal women. Journal of International Medical Research 35(5): 692-695.‏
  • Omrani GR, Masoompour SM, Sadegholvaad A, Larijani B (2006) Effect of menopause and renal function on vitamin D status in Iranian women. EMHJ-Eastern Mediterranean Health Journal 12 (1-2): 188-195, 2006.‏
  • Pala E, Denkçeken T (2019) Differentially expressed circulating miRNAs in postmenopausal osteoporosis: a meta-analysis. Bioscience reports 39(5): BSR20190667.‏
  • Pandey SK, Singh A, Polipalli SK, Gupta S, Kapoor S (2013) Association of Methylene Tetrahydrofolate Reductase Polymorphism with BMD and Homocysteine in Premenopausal North Indian Women. Journal of Clinical and Diagnostic Research: JCDR 7(12): 2908.‏
  • Peacock M (2010) Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology, 5(Supplement 1): S23-S30.‏
  • Penido MGM, Alon US (2012) Phosphate homeostasis and its role in bone health. Pediatric nephrology 27(11): 2039-2048.‏
  • Poursadegh Zonouzi A, Chaparzadeh N, Asghari Estiar M, Mehrzad Sadaghiani M, Farzadi L, Ghasemzadeh A, Sakhinia E (2012) Methylenetetrahydrofolate reductase C677T and A1298C mutations in women with recurrent spontaneous abortions in the Northwest of Iran. ISRN obstetrics and gynecology.
  • Rana AH (2013) Evaluation of serum osteocalcin level in Iraqi postmenopausal women with primary osteoporosis. J Fac Med Baghdad 55: 2.
  • Redmond J, Fulford AJ, Jarjou L, Zhou B, Prentice A, Schoenmakers I (2016) Diurnal rhythms of bone turnover markers in three ethnic groups. The Journal of Clinical Endocrinology & Metabolism 101(8): 3222-3230.‏
  • Redmond J, Jarjou LMA, Zhou B, Prentice A, Schoenmakers I (2014) Ethnic differences in calcium, phosphate and bone metabolism. Proceedings of the Nutrition Society 73(2): 340-351.‏
  • Reid D (2011) Handbook of osteoporosis. Springer Science & Business Media.
  • Reilly R, McNulty H, Pentieva K, Strain JJ, Ward M (2014) MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins? Proceedings of the Nutrition Society 73(1): 47-56.‏
  • Saad MN, Mabrouk MS, Eldeib AM, Shaker OG (2015) Effect of MTHFR, TGFβ1, and TNFB polymorphisms on osteoporosis in rheumatoid arthritis patients. Gene 568(2): 124-128.‏
  • Saffroy R, Lemoine A, Debuire B (2005) MTHFR (5, 10-Methylenetetrahydrofolate reductase). Atlas of Genetics and Cytogenetics in Oncology and Haematology.‏
  • Selvapandian K, Arshiya B, Priya A, Latha J, Santhi N, et al. (2016) Study of bone mineral density and serum vitamin D levels in health postmenopausal women. J Evid Based Med Healthc 3: 3515-3519
  • Shakoor S, Ilyas F, Abbas N, Mirza MA, Arif S (2014) Prevalence of osteoporosis in relation to serum calcium and phosphorus in aging women. J Glob Innov Agric Soc Sci 2(2): 70-75.‏
  • Shiraki M, Urano T, Kuroda T, Saito M, Tanaka S, Miyao-Koshizuka M, Inoue S (2008) The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. Journal of bone and mineral metabolism 26(6): 595-602.‏
  • Soewarlan WDHP, Joenoes H, Bawazier SA, Suryandari DA, Auerkari EI (2019, April) Distribution of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in postmenopausal Indonesian women with osteoporosis–A preliminary study. In AIP Conference Proceedings (2092(1): 030023). AIP Publishing.‏
  • Wasilewski G, Vervloet M, Schurgers LJ (2019) The bone–vasculature axis: calcium supplementation and the role of vitamin K. Frontiers in cardiovascular medicine 6(6).‏
  • Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Investig 102: 274.
  • Yang Y, Fei M, Zhou X, Li Y, Jin D (2019) The association of genetic variants in FGFR2 with osteoporosis susceptibility in Chinese Han population. Bioscience reports 39(6).‏
  • Zetterberg H, Regland B, Palme´r M, et al. (2002) Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet 10(2): 113-118.
  • Zhou X, Li J, Jiang L, Zhou D, Wu L, Huang Y, Xu N (2019) SAA1 gene polymorphisms in osteoporosis patients. Bioscience reports 39(2).‏
  • Zhu K, Prince RL (2015) Lifestyle and osteoporosis. Current osteoporosis reports 13(1): 52-59.‏


This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.