Skip to main content
SpringerLink
Log in

Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish Cohort

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Osteoporosis is a complex disease involving many putative genetic factors. Association analysis of functional SNPs in candidate genes is an important tool for their identification. However, this approach is affected by limited power, population stratification, and other drawbacks that lead to discordant results. Replication in independent cohorts is essential. We performed association analyses of three functional polymorphisms previously associated with bone phenotypes—namely, Ala222Val in MTHFR, Ile1062Val in LRP6, and −13910C>T in LCT—in a cohort of 944 postmenopausal Spanish women, all of them with lumbar spine (LS) bone mineral density (BMD) data and most with femoral neck (FN) BMD and fracture data. We found significant differences between genotypes only for the MTHFR polymorphism and vertebral factures, with an OR of 2.27 (95% CI 1.17–4.38) for the TT vs. CC/CT genotypes, P = 0.018. We present genotype and allele frequency data for LCT −13910C>T for a Spanish population, where the T allele (conferring lactase persistence) has a frequency of 38.6%. Genotype frequencies were consistent with observed clines in Europe and with the prevalence of lactase nonpersistence. The LCT −13910C>T polymorphism was significantly associated with height and weight, such that T allele carriers were 0.88 cm taller (95% CI 0.08–1.59 cm, P = 0.032, adjusted by age) than CC individuals and TT homozygotes were 1.91 kg heavier than CC/CT individuals (95% CI 0.11–3.71 kg, P = 0.038, adjusted by age). In conclusion, no significant association was observed between the studied polymorphisms and LS BMD or FN BMD in postmenopausal Spanish women, and only MTHFR Ala222Val was associated with vertebral fractures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. NIH Consensus Development Panel on Osteoporosis Prevention, Detection, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795

    Article  Google Scholar 

  2. Ralston SH (2002) Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466

    Article  CAS  PubMed  Google Scholar 

  3. 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

    Article  CAS  PubMed  Google Scholar 

  4. Ferrari S (2008) Human genetics of osteoporosis. Best Pract Res Clin Endocrinol Metab 22:723–735

    Article  CAS  PubMed  Google Scholar 

  5. Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N (1991) Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48:536–545

    CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. Geisel J, Zimbelmann I, Schorr H, Knapp JP, Bodis M, Hubner U, Herrmann W (2001) Genetic defects as important factors for moderate hyperhomocysteinemia. Clin Chem Lab Med 39:698–704

    Article  CAS  PubMed  Google Scholar 

  8. Passaro A, Vanini A, Calzoni F, Alberti L, Zamboni PF, Fellin R, Solini A (2001) Plasma homocysteine, methylenetetrahydrofolate reductase mutation and carotid damage in elderly healthy women. Atherosclerosis 157:175–180

    Article  CAS  PubMed  Google Scholar 

  9. Dekou V, Whincup P, Papacosta O, Ebrahim S, Lennon L, Ueland PM, Refsum H, Humphries SE, Gudnason V (2001) The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study. Atherosclerosis 154:659–666

    Article  CAS  PubMed  Google Scholar 

  10. Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH (1996) Evidence for McKusick’s hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1315:159–162

    PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ, Tromp G, Kuivaniemi H, Ala-Kokko L, Prockop DJ, Spotila LD (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 6:151–157

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. Karasik D, Myers RH, Hannan MT, Gagnon D, McLean RR, Cupples LA, Kiel DP (2002) Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos Int 13:796–802

    Article  CAS  PubMed  Google Scholar 

  15. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2006) Meta-analysis of genome-wide linkage studies for bone mineral density. J Hum Genet 51:480–486

    Article  PubMed  Google Scholar 

  16. Huang QY, Li GH, Kung AW (2009) Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese. Bone 44:984–988

    Article  CAS  PubMed  Google Scholar 

  17. 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(Suppl 1):S14

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30:233–237

    Article  CAS  PubMed  Google Scholar 

  21. Wang Y, Harvey CB, Pratt WS, Sams VR, Sarner M, Rossi M, Auricchio S, Swallow DM (1995) The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element. Hum Mol Genet 4:657–662

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Harvey CB, Hollox EJ, Phillips AD, Poulter M, Clay P, Walker-Smith JA, Swallow DM (1998) The genetically programmed down-regulation of lactase in children. Gastroenterology 114:1230–1236

    Article  CAS  PubMed  Google Scholar 

  23. Kuokkanen M, Enattah NS, Oksanen A, Savilahti E, Orpana A, Jarvela I (2003) Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. Gut 52:647–652

    Article  CAS  PubMed  Google Scholar 

  24. Lewinsky RH, Jensen TG, Moller J, Stensballe A, Olsen J, Troelsen JT (2005) T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum Mol Genet 14:3945–3953

    Article  CAS  PubMed  Google Scholar 

  25. Birge SJ Jr, Keutmann HT, Cuatrecasas P, Whedon GD (1967) Osteoporosis, intestinal lactase deficiency and low dietary calcium intake. N Engl J Med 276:445–448

    Article  CAS  PubMed  Google Scholar 

  26. Finkenstedt G, Skrabal F, Gasser RW, Braunsteiner H (1986) Lactose absorption, milk consumption, and fasting blood glucose concentrations in women with idiopathic osteoporosis. BMJ 292:161–162

    Article  CAS  PubMed  Google Scholar 

  27. Horowitz M, Wishart J, Mundy L, Nordin BE (1987) Lactose and calcium absorption in postmenopausal osteoporosis. Arch Intern Med 147:534–536

    Article  CAS  PubMed  Google Scholar 

  28. Vigorita VJ, Lane M, Suda MK, Nelkin M (1987) Differences between lactase deficient and non-lactase deficient women with spinal osteoporosis. Clin Orthop Relat Res 215:248–253

    PubMed  Google Scholar 

  29. Mainguet P, Faille I, Destrebecq L, Devogelaer JP, Nagant de Deuxchaisnes C (1991) Lactose intolerance, calcium intake, and osteopenia. Lancet 338:1156–1157

    Article  CAS  PubMed  Google Scholar 

  30. Slemenda CW, Christian JC, Hui S, Fitzgerald J, Johnston CC Jr (1991) No evidence for an effect of lactase deficiency on bone mass in pre- or postmenopausal women. J Bone Miner Res 6:1367–1371

    Article  CAS  PubMed  Google Scholar 

  31. Corazza GR, Benati G, Di Sario A, Tarozzi C, Strocchi A, Passeri M, Gasbarrini G (1995) Lactose intolerance and bone mass in postmenopausal Italian women. Br J Nutr 73:479–487

    Article  CAS  PubMed  Google Scholar 

  32. Laroche M, Bon E, Moulinier L, Cantagrel A, Mazieres B (1995) Lactose intolerance and osteoporosis in men. Rev Rhum Engl Ed 62:766–769

    CAS  PubMed  Google Scholar 

  33. Honkanen R, Kroger H, Alhava E, Turpeinen P, Tuppurainen M, Saarikoski S (1997) Lactose intolerance associated with fractures of weight-bearing bones in Finnish women aged 38–57 years. Bone 21:473–477

    Article  CAS  PubMed  Google Scholar 

  34. Obermayer-Pietsch BM, Bonelli CM, Walter DE, Kuhn RJ, Fahrleitner-Pammer A, Berghold A, Goessler W, Stepan V, Dobnig H, Leb G, Renner W (2004) Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res 19:42–47

    Article  PubMed  Google Scholar 

  35. Enattah N, Valimaki VV, Valimaki MJ, Loyttyniemi E, Sahi T, Jarvela I (2004) Molecularly defined lactose malabsorption, peak bone mass and bone turnover rate in young Finnish men. Calcif Tissue Int 75:488–493

    Article  CAS  PubMed  Google Scholar 

  36. Enattah N, Pekkarinen T, Valimaki MJ, Loyttyniemi E, Jarvela I (2005) Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women. Eur J Clin Nutr 59:1105–1111

    Article  CAS  PubMed  Google Scholar 

  37. Enattah NS, Sulkava R, Halonen P, Kontula K, Jarvela I (2005) Genetic variant of lactase-persistent C/T-13910 is associated with bone fractures in very old age. J Am Geriatr Soc 53:79–82

    Article  PubMed  Google Scholar 

  38. Laaksonen MM, Impivaara O, Sievanen H, Viikari JS, Lehtimaki TJ, Lamberg-Allardt CJ, Karkkainen MU, Valimaki M, Heikkinen J, Kroger LM, Kroger HP, Jurvelin JS, Kahonen MA, Raitakari OT (2009) Associations of genetic lactase non-persistence and sex with bone loss in young adulthood. Bone 44:1003–1009

    Article  CAS  PubMed  Google Scholar 

  39. Esterle L, Sabatier JP, Guillon-Metz F, Walrant-Debray O, Guaydier-Souquieres G, Jehan F, Garabedian M (2009) Milk, rather than other foods, is associated with vertebral bone mass and circulating IGF-1 in female adolescents. Osteoporos Int 20:567–575

    Article  CAS  PubMed  Google Scholar 

  40. Bacsi K, Kosa JP, Lazary A, Balla B, Horvath H, Kis A, Nagy Z, Takacs I, Lakatos P, Speer G (2009) LCT 13910 C/T polymorphism, serum calcium, and bone mineral density in postmenopausal women. Osteoporos Int 20:639–645

    Article  CAS  PubMed  Google Scholar 

  41. Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209

    Article  CAS  PubMed  Google Scholar 

  42. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407:535–538

    Article  CAS  PubMed  Google Scholar 

  43. Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M, Wahl MB, Galceran J, Grosschedl R, Ozono K, Imai K (2004) Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131:5469–5480

    Article  CAS  PubMed  Google Scholar 

  44. Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO (2004) Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19:2033–2040

    Article  CAS  PubMed  Google Scholar 

  45. van Meurs JB, Rivadeneira F, Jhamai M, Hugens W, Hofman A, van Leeuwen JP, Pols HA, Uitterlinden AG (2006) Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res 21:141–150

    Article  PubMed  CAS  Google Scholar 

  46. De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila ME, Major MB, Myers A, Saez K, Henriquez JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT (2007) Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer’s disease. Proc Natl Acad Sci USA 104:9434–9439

    Article  PubMed  CAS  Google Scholar 

  47. Sims AM, Shephard N, Carter K, Doan T, Dowling A, Duncan EL, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Thomas G, Wass JA, Brown MA (2008) Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res 23:499–506

    Article  CAS  PubMed  Google Scholar 

  48. Bustamante M, Nogues X, Agueda L, Jurado S, Wesselius A, Caceres E, Carreras R, Ciria M, Mellibovsky L, Balcells S, Diez-Perez A, Grinberg D (2007) Promoter 2 −1025 T/C polymorphism in the RUNX2 gene is associated with femoral neck BMD in Spanish postmenopausal women. Calcif Tissue Int 81:327–332

    Article  CAS  PubMed  Google Scholar 

  49. Bustamante M, Nogues X, Mellibovsky L, Agueda L, Jurado S, Caceres E, Blanch J, Carreras R, Diez-Perez A, Grinberg D, Balcells S (2007) Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women. Eur J Endocrinol 157:677–684

    Article  CAS  PubMed  Google Scholar 

  50. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  PubMed  Google Scholar 

  51. Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929

    Article  CAS  PubMed  Google Scholar 

  52. Gauderman WJ (2002) Sample size requirements for association studies of gene–gene interaction. Am J Epidemiol 155:478–484

    Article  PubMed  Google Scholar 

  53. Agueda L, Bustamante M, Jurado S, Garcia-Giralt N, Ciria M, Salo G, Carreras R, Nogues X, Mellibovsky L, Diez-Perez A, Grinberg D, Balcells S (2008) A haplotype-based analysis of the LRP5 gene in relation to osteoporosis phenotypes in Spanish postmenopausal women. J Bone Miner Res 23:1954–1963

    Article  CAS  PubMed  Google Scholar 

  54. 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

    Article  CAS  PubMed  Google Scholar 

  55. Pinto X, Vilaseca MA, Garcia-Giralt N, Ferrer I, Pala M, Meco JF, Mainou C, Ordovas JM, Grinberg D, Balcells S (2001) Homocysteine and the MTHFR 677C–>T allele in premature coronary artery disease. Case control and family studies. Eur J Clin Invest 31:24–30

    Article  CAS  PubMed  Google Scholar 

  56. Rasinpera H, Forsblom C, Enattah NS, Halonen P, Salo K, Victorzon M, Mecklin JP, Jarvinen H, Enholm S, Sellick G, Alazzouzi H, Houlston R, Robinson J, Groop PH, Tomlinson I, Schwartz S Jr, Aaltonen LA, Jarvela I (2005) The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population. Gut 54:643–647

    Article  CAS  PubMed  Google Scholar 

  57. Obermayer-Pietsch B (2006) Genetics of osteoporosis. Wien Med Wochenschr 156:162–167

    Article  PubMed  Google Scholar 

  58. Mulcare C (2006) The evolution of the lactase persistence phenotype. PhD thesis, University of London, London

  59. Baines M, Kredan MB, Usher J, Davison A, Higgins G, Taylor W, West C, Fraser WD, Ranganath LR (2007) The association of homocysteine and its determinants MTHFR genotype, folate, vitamin B12 and vitamin B6 with bone mineral density in postmenopausal British women. Bone 40:730–736

    Article  CAS  PubMed  Google Scholar 

  60. 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

    Article  CAS  PubMed  Google Scholar 

  61. 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

    Article  CAS  PubMed  Google Scholar 

  62. Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, Brixen K, Mosekilde L (2005) Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish Osteoporosis Prevention Study. Bone 36:577–583

    Article  CAS  PubMed  Google Scholar 

  63. 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

    Article  CAS  PubMed  Google Scholar 

  64. Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J (1995) Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 346:85–89

    Article  CAS  PubMed  Google Scholar 

  65. Finkelstein JD (1998) The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 157(Suppl 2):S40–S44

    Article  CAS  PubMed  Google Scholar 

  66. McNulty H, McKinley MC, Wilson B, McPartlin J, Strain JJ, Weir DG, Scott JM (2002) Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am J Clin Nutr 76:436–441

    CAS  PubMed  Google Scholar 

  67. Obermayer-Pietsch BM, Gugatschka M, Reitter S, Plank W, Strele A, Walter D, Bonelli C, Goessler W, Dobnig H, Hogenauer C, Renner W, Fahrleitner-Pammer A (2007) Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption? Osteoporos Int 18:445–451

    Article  CAS  PubMed  Google Scholar 

  68. Diez-Perez A, Gonzalez-Macias J, Marin F, Abizanda M, Alvarez R, Gimeno A, Pegenaute E, Vila J (2007) Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound. Osteoporos Int 18:629–639

    Article  CAS  PubMed  Google Scholar 

  69. Karasik D, Ferrari SL (2008) Contribution of gender-specific genetic factors to osteoporosis risk. Ann Hum Genet 72:696–714

    Article  CAS  PubMed  Google Scholar 

  70. van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290

    Article  PubMed  Google Scholar 

  71. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    Article  CAS  PubMed  Google Scholar 

  72. 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

    Article  CAS  PubMed  Google Scholar 

  73. 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

    Article  CAS  PubMed  Google Scholar 

  74. 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

    Article  CAS  PubMed  Google Scholar 

  75. Villadsen MM, Bunger 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

    Article  CAS  PubMed  Google Scholar 

  76. 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

    Article  CAS  PubMed  Google Scholar 

  77. Nissen N, Madsen JS, Bladbjerg EM, Beck Jensen JE, Jorgensen 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

    Article  CAS  PubMed  Google Scholar 

  78. Jorgensen HL, Madsen JS, Madsen B, Saleh MM, Abrahamsen B, Fenger M, Lauritzen JB (2002) Association of a common allelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures. A case control study in Danish postmenopausal women. Calcif Tissue Int 71:386–392

    Article  CAS  PubMed  Google Scholar 

  79. Bathum L, von Bornemann Hjelmborg J, Christiansen L, Madsen JS, Skytthe A, Christensen K (2004) Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int 15:659–664

    Article  CAS  PubMed  Google Scholar 

  80. 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. J Bone Miner Metab 26:595–602

    Article  CAS  PubMed  Google Scholar 

  81. Gjesdal CG, Vollset SE, Ueland PM, Refsum H, Meyer HE, Tell GS (2007) Plasma homocysteine, folate, and vitamin B12 and the risk of hip fracture: the Hordaland Homocysteine Study. J Bone Miner Res 22:747–756

    Article  CAS  PubMed  Google Scholar 

  82. Valero C, Alonso MA, Zarrabeitia MT, Viadero C, Hernandez JL, Riancho JA (2007) MTHFR C677T polymorphism and osteoporotic fractures. Horm Metab Res 39:543–547

    Article  CAS  PubMed  Google Scholar 

  83. Olds LC, Sibley E (2003) Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum Mol Genet 12:2333–2340

    Article  CAS  PubMed  Google Scholar 

  84. Enattah NS, Trudeau A, Pimenoff V, Maiuri L, Auricchio S, Greco L, Rossi M, Lentze M, Seo JK, Rahgozar S, Khalil I, Alifrangis M, Natah S, Groop L, Shaat N, Kozlov A, Verschubskaya G, Comas D, Bulayeva K, Mehdi SQ, Terwilliger JD, Sahi T, Savilahti E, Perola M, Sajantila A, Jarvela I, Peltonen L (2007) Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans. Am J Hum Genet 81:615–625

    Article  CAS  PubMed  Google Scholar 

  85. Swallow DM (2003) Genetics of lactase persistence and lactose intolerance. Annu Rev Genet 37:197–219

    Article  CAS  PubMed  Google Scholar 

  86. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111–1120

    Article  CAS  PubMed  Google Scholar 

  87. Almon R, Engfeldt P, Tysk C, Sjostrom M, Nilsson TK (2007) Prevalence and trends in adult-type hypolactasia in different age cohorts in central Sweden diagnosed by genotyping for the adult-type hypolactasia-linked LCT −13910C>T mutation. Scand J Gastroenterol 42:165–170

    Article  CAS  PubMed  Google Scholar 

  88. Bacsi K, Hitre E, Kosa JP, Horvath H, Lazary A, Lakatos PL, Balla B, Budai B, Lakatos P, Speer G (2008) Effects of the lactase 13910 C/T and calcium-sensor receptor A986S G/T gene polymorphisms on the incidence and recurrence of colorectal cancer in Hungarian population. BMC Cancer 8:317

    Article  PubMed  CAS  Google Scholar 

  89. Mottes M, Belpinati F, Milani M, Saccomandi D, Petrelli E, Calacoci M, Chierici R, Pignatti PF, Borgna-Pignatti C (2008) Genetic testing for adult-type hypolactasia in Italian families. Clin Chem Lab Med 46:980–984

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to M. Cozar for technical help and R. Rycroft for revising the English. They also thank B. Obermayer for sharing the LCT genotyping assay information. L. A. is the recipient of a fellowship from the Catalan government. This study was supported by grants from the Carlos III Health Institute (ISCIII), Spanish Ministry of Science and Innovation (PI030708), Spanish Ministry of Education and Science (SAF2007-64654), and Catalan government (2005SGR 00848 and 2009SGR971). The authors are also grateful for the support from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and the Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), which are initiatives of the ISCIII.

Author information

Authors and Affiliations

  1. Department of Genetics, Faculty of Biology, University of Barcelona, Barcelona, Spain

    Lídia Agueda, Roser Urreizti, Mariona Bustamante, Daniel Grinberg & Susana Balcells

  2. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain

    Lídia Agueda, Roser Urreizti, Mariona Bustamante, Daniel Grinberg & Susana Balcells

  3. CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain

    Lídia Agueda, Roser Urreizti, Mariona Bustamante, Daniel Grinberg & Susana Balcells

  4. Internal Medicine, URFOA, IMIM, Hospital del Mar, Autonomous University of Barcelona, Barcelona, Spain

    Susana Jurado, Natàlia Garcia-Giralt, Adolfo Díez-Pérez, Xavier Nogués & Leonardo Mellibovsky

  5. Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Barcelona, Spain

    Susana Jurado, Natàlia Garcia-Giralt, Adolfo Díez-Pérez, Xavier Nogués & Leonardo Mellibovsky

Authors
  1. Lídia Agueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roser Urreizti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariona Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susana Jurado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natàlia Garcia-Giralt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adolfo Díez-Pérez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xavier Nogués
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonardo Mellibovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel Grinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susana Balcells
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susana Balcells.

Additional information

The authors have stated that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agueda, L., Urreizti, R., Bustamante, M. et al. Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish Cohort. Calcif Tissue Int 87, 14–24 (2010). https://doi.org/10.1007/s00223-010-9361-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-010-9361-4

Keywords

Search

Navigation