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Klotho Gene Polymorphisms are Associated with Osteocalcin Levels but not Bone Density of Aged Postmenopausal Women

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Abstract

Osteoporosis is known to have a strong genetic basis. It has been proposed that polymorphisms within the KL (klotho) gene have a significant effect on aging, in particular, the osteoblast defect of aging. The association between polymorphisms within this gene and biochemical markers of bone formation and resorption, bone structure, and fracture rates was studied in 1,190 postmenopausal women with a mean age of 75 years. Genotyping of these polymorphic sites was carried out using Matrix-Assisted Laser Desorption Ionization—Time of Flight (MALDI-ToF) mass spectrometry. The G allele of SNP c.1775G>A was associated with a lower osteocalcin level than the A allele (P = 0.004) in a codominant model. SNPs C-387T and IVS1+8262c>t both showed nonsignificant associations with osteocalcin (P values of 0.063 and 0.068, respectively), but a haplotype analysis of 2 of 5 haplotypes of the three SNPs with a frequency greater than 4% revealed a significant association with osteocalcin (P = 0.036). None of the individual polymorphisms or haplotypes analyzed showed any associations with a marker of bone resorption the deoxypyridinoline creatinine ratio, bone structure, or fracture data. Therefore, the G polymorphism within the c.1775G>A SNP site and a haplotype including this are associated with a reduced osteoblast product osteocalcin. These data suggest that variation in the KL gene product affects osteoblast activity independent of osteoclast activity but that this defect does not result in an effect on bone structure in this population, perhaps because of “rescue” by other genetic or environmental factors in this population.

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References

  1. Kanis JA, Melton LJ, 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141

    PubMed  Google Scholar 

  2. Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Wahner HW, Riggs BL (1993) Long-term fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res 8:1227–1233

    PubMed  Google Scholar 

  3. Aloia JF, Cohn SH, Vaswani A, Yeh JK, Yuen K, Ellis K (1985) Risk factors for postmenopausal osteoporosis. Am J Med 78:95–100

    Article  Google Scholar 

  4. 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 109:870–873

    PubMed  Google Scholar 

  5. 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 10:1607–1613

    PubMed  Google Scholar 

  6. Krall EA, Dawson-Hughes B (1993) Heritable and life-style determinants of bone mineral density. J Bone Miner Res 8:1–9

    PubMed  Google Scholar 

  7. 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

    Google Scholar 

  8. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr. (1973) Genetic factors in determining bone mass. J Clin Invest 52:2800–2808

    PubMed  Google Scholar 

  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 10:558–567

    PubMed  Google Scholar 

  10. 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:E320–327

    PubMed  Google Scholar 

  11. Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H (2002) Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 17:1744–1751

    PubMed  Google Scholar 

  12. Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237

    PubMed  Google Scholar 

  13. Randall AG, Kent GN, Garcia-Webb P, Bhagat CI, Pearce DJ, Gutteridge DH, Prince RL, Stewart G, Stuckey B, Will RK, Retallack RW, Price RI, Ward L (1996) Comparison of biochemical markers of bone turnover in Paget disease treated with pamidronate and a proposed model for the relationships between measurements of the different forms of pyridinoline cross-links. J Bone Miner Res 11:1176–1184

    PubMed  Google Scholar 

  14. 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 31:497–502

    Article  PubMed  Google Scholar 

  15. Bollerslev J, Wilson SG, Dick IM, Devine A, Dhaliwal SS, Prince RL (2004) Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women. Calcif Tissue Int 74:12–17. Epub 2003 Sep 2029

    Article  PubMed  Google Scholar 

  16. 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 Pacific J Clin Nutr 3:19–31

    Google Scholar 

  17. Price PA, Nishimoto SK (1980) Radioimmunoassay for the vitamin K-dependent protein of bone and its discovery in plasma. Proc Natl Acad Sci USA 77:2234–2238

    PubMed  Google Scholar 

  18. Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121

    Article  PubMed  Google Scholar 

  19. Mitchell BD, Cole S A, Bauer RL, Iturria S J, Rodriguez EA, Blangero J, MacCluer JW, Hixson JE (2000) Genes influencing variation in serum osteocalcin concentrations are linked to markers on chromosomes 16q and 20q. J Clin Endocrinol Metab 85:1362–1366

    Article  PubMed  Google Scholar 

  20. Zhou H, Choong P, McCarthy R, Chou ST, Martin TJ, Ng KW (1994) In situ hybridization to show sequential expression of osteoblast gene markers during bone formation in vivo. J Bone Miner Res 9:1489–1499

    PubMed  Google Scholar 

  21. Seibel MJ (2000) Molecular markers of bone turnover: biochemical, technical and analytical aspects. Osteoporos Int 11 Suppl 6:S18–29

    Article  Google Scholar 

  22. Khosla S, Kleerekoper M (1999) Biochemical markers of bone turnover. In: Favus MJ (ed). Primer on the metabolic bone diseases and disorders of mineral metabolism. Philadelphia: Lippincott, Williams & Wilkins, pp 128–134

    Google Scholar 

  23. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (1998) Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242:626–630

    Article  PubMed  Google Scholar 

  24. 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 10:2017–2022

    PubMed  Google Scholar 

  25. 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 33:335–341

    Article  PubMed  Google Scholar 

  26. 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 16:1634–1641

    PubMed  Google Scholar 

  27. 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 107:899–907

    PubMed  Google Scholar 

  28. 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 74:866–875. Epub 2004 Apr 2007

    Article  PubMed  Google Scholar 

  29. 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 49:80–86. Epub 2004 Jan 2015

    Article  PubMed  Google Scholar 

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Acknowledgement

The study was supported by research grants from Health-way Health Promotion Foundation of Western Australia, the Australian Menopause Society, the Sir Charles Gairdner Hospital Research Fund, and National

Health and Medical Research Council of Australia, grant no. 254627 and 294402.

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Authors and Affiliations

  1. School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, USA

    S.G. Wilson, F.M.A. Islam, I.M. Dick, A. Devine & R.L. Prince

  2. Dept.of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, WA, USA

    B.H. Mullin, S.G. Wilson, M. Calautti, I.M. Dick, A. Devine & R.L. Prince

  3. Western Australian Institute of Medical Research, Sir Charles Gairdner Hospital, Nedlands, WA, USA

    S.G. Wilson, F.M.A. Islam, I.M. Dick, A. Devine & R.L. Prince

Authors
  1. B.H. Mullin
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  2. S.G. Wilson
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  3. F.M.A. Islam
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  4. M. Calautti
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  5. I.M. Dick
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  6. A. Devine
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  7. R.L. Prince
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Correspondence to R.L. Prince.

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Mullin, B., Wilson, S., Islam, F. et al. Klotho Gene Polymorphisms are Associated with Osteocalcin Levels but not Bone Density of Aged Postmenopausal Women. Calcif Tissue Int 77, 145–151 (2005). https://doi.org/10.1007/s00223-004-0291-x

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  • DOI: https://doi.org/10.1007/s00223-004-0291-x

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