Calcified Tissue International

, Volume 81, Issue 1, pp 10–17 | Cite as

Polymorphisms in ALOX12, but not ALOX15, Are Significantly Associated With BMD in Postmenopausal Women

  • B. H. Mullin
  • T. D. Spector
  • C. C. Curtis
  • G. N. Ong
  • D. J. Hart
  • A. J. Hakim
  • T. Worthy
  • S. G. Wilson


The murine arachidonate 15-lipoxygenase gene (Alox15) has recently been identified as a negative regulator of peak bone mineral density (BMD). The human ALOX15 gene shares significant sequence homology with the murine Alox15 gene; however, the human arachidonate 12-lipoxygenase gene (ALOX12) is functionally more similar to the mouse gene. Multiple single-nucleotide polymorphisms (SNPs) in the human ALOX15 and ALOX12 genes have previously been reported to be significantly associated with BMD in humans. On the basis of these data, we carried out our own investigation of the human ALOX15 and ALOX12 genes and their relationship with hip and spine BMD parameters. The study population consisted of 779 postmenopausal women with a mean (± standard deviation) age of 62.5 ± 5.9 years at BMD measurement and was recruited from a single large general practice in Chingford, northeast London. Three SNPs from ALOX15 and five from ALOX12 were analyzed. None of the SNPs that we analyzed in ALOX15 were significantly associated with any of the BMD parameters or fracture data. However, we found that three SNPs from ALOX12, all previously associated with spine BMD in women, were significantly associated with spine and various hip BMD parameters in our cohort (P = 0.029–0.049). In conclusion, we found no association between polymorphism in ALOX15 and BMD phenotypes but were able to replicate previous findings that genetic variation in ALOX12 seems to play a role in determining bone structure in Caucasian women.


Bone mineral density ALOX15 ALOX12 Osteoporosis 


  1. 1.
    Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141PubMedGoogle Scholar
  2. 2.
    Prince RL, Dick I (1997) Oestrogen effects on calcium membrane transport: a new view of the inter-relationship between oestrogen deficiency and age-related osteoporosis. Osteoporos Int 7(suppl 3):S150–S154PubMedGoogle Scholar
  3. 3.
    Evans RA, Marel GM, Lancaster EK, Kos S, Evans M, Wong SY (1988) Bone mass is low in relatives of osteoporotic patients. Ann Intern Med 109:870–873PubMedGoogle Scholar
  4. 4.
    Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD (1995) Bone density determinants in elderly women: a twin study. J Bone Miner Res 10:1607–1613PubMedGoogle Scholar
  5. 5.
    Krall EA, Dawson-Hughes B (1993) Heritable and life-style determinants of bone mineral density. J Bone Miner Res 8:1–9PubMedGoogle Scholar
  6. 6.
    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 80:706–710PubMedGoogle Scholar
  7. 7.
    Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr (1973) Genetic factors in determining bone mass. J Clin Invest 52:2800–2808PubMedGoogle Scholar
  8. 8.
    Seeman E, Hopper JL, Young NR, Formica C, Goss P, Tsalamandris C (1996) Do genetic factors explain associations between muscle strength, lean mass, and bone density? A twin study. Am J Physiol 270:E320–E327PubMedGoogle Scholar
  9. 9.
    Young D, Hopper JL, Nowson CA, Green RM, Sherwin AJ, Kaymakci B, Smid M, Guest CS, Larkins RG, Wark JD (1995) Determinants of bone mass in 10- to 26-year-old females: a twin study. J Bone Miner Res 10:558–567PubMedGoogle Scholar
  10. 10.
    Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL (2005) Genetic liability to fractures in the elderly. Arch Intern Med 165:1825–1830PubMedCrossRefGoogle Scholar
  11. 11.
    Gueguen R, Jouanny P, Guillemin F, Kuntz C, Pourel J, Siest G (1995) Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res 10:2017–2022PubMedCrossRefGoogle Scholar
  12. 12.
    Dick IM, Devine A, Marangou A, Dhaliwal SS, Laws S, Martins RN, Prince RL (2002) Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women. Bone 31:497–502PubMedCrossRefGoogle Scholar
  13. 13.
    Dick IM, Devine A, Li S, Dhaliwal SS, Prince RL (2003) The T869C TGF beta polymorphism is associated with fracture, bone mineral density, and calcaneal quantitative ultrasound in elderly women. Bone 33:335–341PubMedCrossRefGoogle Scholar
  14. 14.
    MacDonald HM, McGuigan FA, New SA, Campbell MK, Golden MH, Ralston SH, Reid DM (2001) COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss. J Bone Miner Res 16:1634–1641PubMedCrossRefGoogle Scholar
  15. 15.
    Mann V, Hobson EE, Li B, Stewart TL, Grant SF, Robins SP, Aspden RM, Ralston SH (2001) A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 107:899–907PubMedCrossRefGoogle Scholar
  16. 16.
    Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE (2004) Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet 74:866–875PubMedCrossRefGoogle Scholar
  17. 17.
    Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K (2004) LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 49:80–86PubMedCrossRefGoogle Scholar
  18. 18.
    Deng HW, Xu FH, Huang QY, Shen H, Deng H, Conway T, Liu YJ, Liu YZ, Li JL, Zhang HT, Davies KM, Recker RR (2002) A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis. J Clin Endocrinol Metab 87:5151–5159PubMedCrossRefGoogle Scholar
  19. 19.
    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 6:151–157PubMedCrossRefGoogle Scholar
  20. 20.
    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 10:2447–2452PubMedCrossRefGoogle Scholar
  21. 21.
    Devoto M, Spotila LD, Stabley DL, Wharton GN, Rydbeck H, Korkko J, Kosich R, Prockop D, Tenenhouse A, Sol-Church K (2005) Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density. Eur J Hum Genet 13:781–788PubMedCrossRefGoogle Scholar
  22. 22.
    Kammerer CM, Schneider JL, Cole SA, Hixson JE, Samollow PB, O’Connell JR, Perez R, Dyer TD, Almasy L, Blangero J, Bauer RL, Mitchell BD (2003) Quantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans. J Bone Miner Res 18:2245–2252PubMedCrossRefGoogle Scholar
  23. 23.
    Karasik D, Cupples LA, Hannan MT, Kiel DP (2004) Genome screen for a combined bone phenotype using principal component analysis: the Framingham Study. Bone 34:547–556PubMedCrossRefGoogle Scholar
  24. 24.
    Karasik D, Myers RH, Cupples LA, Hannan MT, Gagnon DR, Herbert A, Kiel DP (2002) Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res 17:1718–1727PubMedCrossRefGoogle Scholar
  25. 25.
    Koller DL, Econs MJ, Morin PA, Christian JC, Hui SL, Parry P, Curran ME, Rodriguez LA, Conneally PM, Joslyn G, Peacock M, Johnston CC, Foroud T (2000) Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis. J Clin Endocrinol Metab 85:3116–3120PubMedCrossRefGoogle Scholar
  26. 26.
    Ralston SH, Galwey N, MacKay I, Albagha OM, Cardon L, Compston JE, Cooper C, Duncan E, Keen R, Langdahl B, McLellan A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass J, Bennett ST (2005) Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS Study. Hum Mol Genet 14:943–951PubMedCrossRefGoogle Scholar
  27. 27.
    Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1:E69PubMedCrossRefGoogle Scholar
  28. 28.
    Wilson SG, Reed PW, Bansal A, Chiano M, Lindersson M, Langdown M, Prince RL, Thompson D, Thompson E, Bailey M, Kleyn PW, Sambrook P, Shi MM, Spector TD (2003) Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet 72:144–155PubMedCrossRefGoogle Scholar
  29. 29.
    Wynne F, Drummond FJ, Daly M, Brown M, Shanahan F, Molloy MG, Quane KA (2003) Suggestive linkage of 2p22-25 and 11q12-13 with low bone mineral density at the lumbar spine in the Irish population. Calcif Tissue Int 72:651–658PubMedCrossRefGoogle Scholar
  30. 30.
    Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos AS, Shea M, Waters RV, Belknap JK, Peltz G, Orwoll ES (2004) Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303:229–232PubMedCrossRefGoogle Scholar
  31. 31.
    Ichikawa S, Koller DL, Johnson ML, Lai D, Xuei X, Edenberg HJ, Klein RF, Orwoll ES, Hui SL, Foroud TM, Peacock M, Econs MJ (2006) Human ALOX12, but not ALOX15, is associated with BMD in white men and women. J Bone Miner Res 21:556–564PubMedCrossRefGoogle Scholar
  32. 32.
    Urano T, Shiraki M, Fujita M, Hosoi T, Orimo H, Ouchi Y, Inoue S (2005) Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5’-flanking region (-5229G/A) with bone mineral density. J Bone Miner Metab 23:226–230PubMedCrossRefGoogle Scholar
  33. 33.
    Xiong DH, Shen H, Zhao LJ, Xiao P, Yang TL, Guo Y, Wang W, Guo YF, Liu YJ, Recker RR, Deng HW (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 21:1678–1695PubMedCrossRefGoogle Scholar
  34. 34.
    Arden NK, Griffiths GO, Hart DJ, Doyle DV, Spector TD (1996) The association between osteoarthritis and osteoporotic fracture: the Chingford Study. Br J Rheumatol 35:1299–1304PubMedCrossRefGoogle Scholar
  35. 35.
    Hart DJ, Spector TD (1993) The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol 20:331–335PubMedGoogle Scholar
  36. 36.
    Ireland P, Jolley D, Giles G, O’Dea K, Powles J, Ritishauser I, Wahlqvist ML, Williams J (1994) Development of the Melbourne FFQ: a food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pac J Clin Nutr 3:19–31Google Scholar
  37. 37.
    International HapMap Project (2003) Nature 426:789–796Google Scholar
  38. 38.
    Carter KW, McCaskie PA, Palmer LJ (2006) JLIN: a Java-based linkage disequilibrium plotter. BMC Bioinformatics 7:60PubMedCrossRefGoogle Scholar
  39. 39.
    Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121PubMedCrossRefGoogle Scholar
  40. 40.
    Chen XS, Kurre U, Jenkins NA, Copeland NG, Funk CD (1994) cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases. J Biol Chem 269:13979–13987PubMedGoogle Scholar
  41. 41.
    Kuhn H, Barnett J, Grunberger D, Baecker P, Chow J, Nguyen B, Bursztyn-Pettegrew H, Chan H, Sigal E (1993) Overexpression, purification and characterization of human recombinant 15-lipoxygenase. Biochim Biophys Acta 1169:80–89PubMedGoogle Scholar
  42. 42.
    Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL (2002) Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143:2376–2384PubMedCrossRefGoogle Scholar
  43. 43.
    Khan E, Abu-Amer Y (2003) Activation of peroxisome proliferator-activated receptor-gamma inhibits differentiation of preosteoblasts. J Lab Clin Med 142:29–34PubMedCrossRefGoogle Scholar
  44. 44.
    Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846–855PubMedCrossRefGoogle Scholar
  45. 45.
    Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680–687PubMedGoogle Scholar
  46. 46.
    Tintut Y, Parhami F, Le V, Karsenty G, Demer LL (1999) Inhibition of osteoblast-specific transcription factor Cbfa1 by the cAMP pathway in osteoblastic cells. Ubiquitin/proteasome-dependent regulation. J Biol Chem 274:28875–28879PubMedCrossRefGoogle Scholar
  47. 47.
    Turek JJ, Watkins BA, Schoenlein IA, Allen KG, Hayek MG, Aldrich CG (2003) Oxidized lipid depresses canine growth, immune function, and bone formation. J Nutr Biochem 14:24–31PubMedCrossRefGoogle Scholar
  48. 48.
    Meunier P, Aaron J, Edouard C, Vignon G (1971) Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop Relat Res 80:147–154PubMedCrossRefGoogle Scholar
  49. 49.
    Burkhardt R, Kettner G, Bohm W, Schmidmeier M, Schlag R, Frisch B, Mallmann B, Eisenmenger W, Gilg T (1987) Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone 8:157–164PubMedCrossRefGoogle Scholar
  50. 50.
    Altman DG (1982) How large a sample? In: Gore SM, Altman DG (eds), Statistics in Practice. British Medical Association, London, pp 21–24Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • B. H. Mullin
    • 1
  • T. D. Spector
    • 2
  • C. C. Curtis
    • 1
  • G. N. Ong
    • 1
  • D. J. Hart
    • 2
  • A. J. Hakim
    • 3
  • T. Worthy
    • 2
  • S. G. Wilson
    • 1
    • 4
    • 5
  1. 1.Department of Endocrinology and DiabetesSir Charles Gairdner HospitalNedlandsAustralia
  2. 2.Twin & Genetic Epidemiology Research UnitSt. Thomas’ HospitalLondonUK
  3. 3.Whipps Cross University HospitalLondonUK
  4. 4.School of Medicine and PharmacologyUniversity of Western AustraliaNedlandsAustralia
  5. 5.Western Australian Institute of Medical ResearchSir Charles Gairdner HospitalNedlandsAustralia

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