Abstract
Many studies have reported an association between the methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism and reduced bone mineral density (BMD), but results have been inconsistent. We, therefore, performed a meta-analysis to further explore this association. Twenty-one studies, comprising 33,045 subjects, analyzed the association of MTHFR c.677C>T with femoral neck BMD. Significant association with reduced BMD was observed in Caucasians (recessive model: WMD = −0.004 g/cm2, 95 % CI −0.008 to −0.006), post-menopausal women (recessive model: WMD = −0.005 g/cm2, 95 % CI −0.007 to −0.003), men (dominant model: WMD = −0.004 g/cm2, 95 % CI −0.005 to −0.004; recessive model: WMD = −0.004 g/cm2, 95 % CI −0.005 to −0.004; TT vs. CC: WMD = −0.006 g/cm2, 95 % CI −0.006 to −0.006; CT vs. CC: WMD = −0.003 g/cm2, 95 % CI −0.003 to −0.003), and cohort studies (recessive model: WMD = −0.003 g/cm2, 95 % CI −0.006 to −0.001). Twenty-two studies, which included 32,271 subjects, analyzed the MTHFR c.677C>T association with lumbar spine BMD. Significant association with reduced BMD was observed in Caucasians, women, post-menopausal women, men, and cohort studies. Seven studies, comprising 6806 subjects, analyzed the MTHFR c.677C>T association with total hip BMD, but no significant association was observed in any population. Nine studies involving 5591 subjects analyzed the association with total body BMD. Significant association with reduced BMD was observed in overall and women subgroup analyses. In summary, this meta-analysis indicates that the MTHFR c.677C>T polymorphism is associated with reduced BMD in lumbar spine and femoral neck in Caucasians, post-menopausal women, and men, and with total body BMD in women. In addition, our results suggest that new studies examining the association between MTHFR c.677C>T polymorphism and BMD of lumbar spine and femoral neck in Asians is warranted, because I 2 > 75.0 % was observed.
Similar content being viewed by others
References
Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, Brixen K, 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. J Bone Miner Res 18:723–729
Abrahamsen B, Jørgensen HL, Nielsen TL, Andersen M, Haug E, Schwarz P, Hagen C, Brixen K (2006) MTHFR c.677C>T polymorphism as an independent predict or of peak bone mass in Danish men—results from the Odense Androgen Study. Bone 38:215–219
Agueda L, Urreizti R, Bustamante M, Jurado S, Garcia-Giralt N, Díez-Pérez A, Nogués X, Mellibovsky L, Grinberg D, Balcells S (2010) Analysis of three functional polymorphisms in relation to osteoporosis phenotypes: replication in a Spanish cohort. Calcif Tissue Int 87:14–24
Bagley PJ, Selhub J (1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA 95:13217–13220
Brambila-Tapia AJ, Durán-González J, Sandoval-Ramírez L, Mena JP, Salazar-Páramo M, Gámez-Nava JI, González-López L, Lazalde-Medina BB, Dávalos NO, Peralta-Leal V, Vázquez del Mercado M, Beltrán-Miranda CP, Dávalos IP (2012) MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. Dis Markers 32:109–114
Consensus Development Conference (1993) Diagnosis prophylactics and treatment of osteoporosis. Am J Med 94:646–650
Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM (1993) Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet 341:962–963
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Devoto M, Specchia C, Li HH, Caminis J, Tenenhouse A, Rodriguez H, Spotila LD (2001) Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum Mol Genet 10:2447–2452
Egger M, Smith DG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315:629–634
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
Golbahar J, Hamidi A, Aminzadeh MA, Omrani GR (2004) Association of plasma folate, plasma total homocysteine, but not methylenetetrahydrofolate reductase C667T polymorphism, with bone mineral density in postmenopausal Iranian women: a cross-sectional study. Bone 35:760–765
Hak AE, Polderman KH, Westendorp IC, Jakobs C, Hofman A, Witteman JC, Stehouwer CD (2000) Increased plasma homocysteine after menopause. Atherosclerosis 149:163–168
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analysis. Br Med J 327:557–560
Hong X, Hsu YH, Terwedow H, Tang G, Liu X, Jiang S, Xu X, Xu X (2007) Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women. Bone 40:737–742
Kang SS, Wong PW, Zhou JM, Sora J, Lessick M, Ruggie N, Grcevich G (1988) Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 37:611–613
Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D (2007) Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet 8:S14
Li M, Lau EM, Woo J (2004) Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women. Bone 35:1369–1374
Macdonald HM, McGuigan FE, Fraser WD, New SA, Ralston SH, Reid DM (2004) Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density. Bone 35:957–964
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. Natl Cancer Inst 22:719–748
McLean RR, Karasik D, Selhub J, Tucker KL, Ordovas JM, Russo GT, Cupples LA, Jacques PF, Kiel DP (2004) Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. J Bone Miner Res 19:410–418
Miyao M, Morita H, Hosoi T, Kurihara H, Inoue S, Hoshino S, Shiraki M, Yazaki Y, Ouchi Y (2000) Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 66:190–194
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795
Nissen N, Madsen JS, Bladbjerg EM, Beck Jensen JE, Jørgensen NR, Langdahl B, Abrahamsen B, Brixen K (2009) No association between hip geometry and four common polymorphisms associated with fracture: the Danish osteoporosis prevention study. Calcif Tissue Int 84:276–285
Oishi Y, Watanabe Y, Shinoda S, Naka M, Ozawa Y, Matsuyama T, Morozumi K, Fuke Y (2012) The IL6 gene polymorphism -634C>G and IL17F gene polymorphism 7488T>C influence bone mineral density in young and elderly Japanese women. Gene 504:75–83
Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP (2005) Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2:e334
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. J Clin Diagn Res 7:2908–2911
Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults: A twin study. J Clin Invest 80:706–710
Ralston SH (2002) Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466
Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512
Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206
Shin MH, Choi JS, Rhee JA, Lee YH, Nam HS, Jeong SK, Park KS, Kim HY, Ryu SY, Choi SW, Song HR, Kim HN, Cauley JA, Kweon SS (2013) Association between methylenetetrahydrofolate reductase C677T polymorphism and bone mineral density: the Dong-gu Study and the Namwon Study. J Korean Med Sci 28:965–968
Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365
Tongboonchoo C, Tungtrongchitr A, Phonrat B, Preutthipan S, Tungtrongchitr R (2013) Association of MTHFR C677T polymorphism with bone mineral density of osteoporosis in postmenopausal Thai women. J Med Assoc Thai 96:133–139
Villadsen MM, Bünger MH, Carstens M, Stenkjaer L, Langdahl BL (2005) Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD. Osteoporos Int 16:411–416
Wang H, Liu C (2012) Association of MTHFR C667T polymorphism with bone mineral density and fracture risk: an updated meta-analysis. Osteoporos Int 23:2625–2634
Yazdanpanah N, Uitterlinden AG, Zillikens MC, Jhamai M, Rivadeneira F, Hofman A, de Jonge R, Lindemans J, Pols HA, van Meurs JB (2008) Low dietary riboflavin but not folate predicts increased fracture risk in postmenopausal women homozygous for the MTHFR 677 T allele. J Bone Miner Res 23:86–94
Zhu K, Beilby J, Dick IM, Devine A, SoósM Prince RL (2009) The effects of homocysteine and MTHFR genotype on hip bone loss and fracture risk in elderly women. Osteoporos Int 20:1183–1191
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors have no conflicts of interest.
Ethical standards
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Communicated by S. Hohmann.
H.-Z. Li and W. Wang contributed equally to this study and should be considered as co-first authors.
Rights and permissions
About this article
Cite this article
Li, HZ., Wang, W., Liu, YL. et al. Association between the methylenetetrahydrofolate reductase c.677C>T polymorphism and bone mineral density: an updated meta-analysis. Mol Genet Genomics 291, 169–180 (2016). https://doi.org/10.1007/s00438-015-1101-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-015-1101-z