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Genetic analysis of serum osteocalcin and bone mineral in multigenerational Afro-Caribbean families

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Abstract

Summary

Osteocalcin is a major component of bone matrix. Concentrations of total, carboxylated, and uncarboxylated osteocalcin, are highly heritable and genetically correlated with bone mineral content (BMC) within African ancestry families.

Introduction

Osteocalcin (OC) is a protein constituent of bone matrix and a marker of bone formation. We characterized the heritability of serum OC measures and identified genomic regions potentially involved in the regulation of OC via high-density genome-wide linkage analysis in African ancestry individuals.

Methods

African ancestry individuals (n = 459) were recruited, without regard to health status, from seven probands (mean family size = 66; 4,373 relative pairs). Residual heritability of serum OC measures was estimated and multipoint quantitative trait linkage analysis was performed using pedigree-based maximum likelihood methods.

Results

Residual heritabilities of total OC, uncarboxylated OC, carboxylated OC and percent uncarboxylated OC were 0.74 ± 0.10, 0.89 ± 0.08, 0.46 ± 0.10 and 0.41 ± 0.09, respectively. All OC measures were genetically correlated with whole body BMC. We obtained strong evidence of bivariate linkage for percent uncarboxylated OC and whole body BMC on chromosome 17 (logarithm of the odds [LOD] = 3.15, 99 cM).

Conclusions

All forms of OC were highly heritable and genetically correlated with total body BMC in these African ancestry families. The identified linkage region contains several candidate genes for bone and energy metabolism including COL1A1 and TNFRSF11A. Further studies of this genomic region may reveal novel insight into the genetic regulation of OC and bone mineralization.

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References

  1. Lian JB, Gundberg CM (1988) Biochemical considerations and clinical applications. Clin Orthop 226:267–291

    PubMed  CAS  Google Scholar 

  2. Price PA, Parthemore JG, Deftos LI, Nishimoto SK (1980) New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone gla protein in the plasma of normal subjects and patients with bone disease. J Clin Invest 66:878–883

    Article  PubMed  CAS  Google Scholar 

  3. Mitchell BD, Cole SA, Bauer RL, Iturria SJ, 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  CAS  Google Scholar 

  4. Kelly PJ, Hopper JL, Macaskill GT, Pocock NA, Sambrook PN, Eisman JA (1991) Genetic factors in bone turnover. J Clin Endocrinol Metab 72:808–813

    Article  PubMed  CAS  Google Scholar 

  5. Havill LM, Rogers J, Cox LA, Mahaney MC (2006) QTL with pleiotropic effects on serum levels of bone-specific alkaline phosphatase and osteocalcin maps to the baboon ortholog of human chromosome 6p23-21.3. J Bone Miner Res 21:1888–1896

    Article  PubMed  CAS  Google Scholar 

  6. Havill LM, Cox LA, Rogers J, Mahaney MC (2005) Cross-species replication of a serum osteocalcin quantitative trait locus on human chromosome 16q in pedigreed baboons. Calcif Tissue Int 77:205–211

    Article  PubMed  CAS  Google Scholar 

  7. Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD (1996) Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab 81:140–146

    Article  PubMed  CAS  Google Scholar 

  8. Shea MK, Benjamin EJ, Dupuis J, Massaro JM, Jacques PF, D'Agostino RB Sr, Ordovas JM, O'Donnell CJ, Dawson-Hughes B, Vasan RS, Booth SL (2009) Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr 63:458–464

    Article  PubMed  CAS  Google Scholar 

  9. McGuigan F, Kumar J, Ivaska KK, Obrant KJ, Gerdhem P, Akesson K (2010) Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification. J Bone Miner Res. doi:10.1002/jmbr.32

  10. Lorentzon M, Lorentzon R, Nordstram P (2001) Vitamin D receptor gene polymorphism is related to bone density, circulating osteocalcin, and parathyroid hormone in healthy adolescent girls. J Bone Miner Metab 19:302–307

    Article  PubMed  CAS  Google Scholar 

  11. Nakamura M, Morimoto S, Ishii A, Higuchi T, Ogihara T, Kakudo K (2006) Cytosine–adenine repeat polymorphism at calcitonin gene locus associated with serum osteocalcin level in Japanese women. Cell Mol Biol 30:15–18

    Google Scholar 

  12. Mullin BH, Wilson SG, Islam FM, Calautti M, Dick IM, Devine A, Prince RL (2005) Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women. Calcif Tissue Int 77:145–151

    Article  PubMed  CAS  Google Scholar 

  13. Lau HH, Ho AY, Luk KD, Kung AW (2004) Transforming growth factor-beta1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in southern Chinese women. Calcif Tissue Int 74:516–521

    Article  PubMed  CAS  Google Scholar 

  14. Ferland G (1998) The vitamin K-dependent proteins: an update. Nutr Rev 56:223–230

    Article  PubMed  CAS  Google Scholar 

  15. Gundberg CM, Looker AC, Nieman SD, Calvo MS (2002) Patterns of osteocalcin and bone specific alkaline phosphatase by age, gender, and race or ethnicity. Bone 31:703–708

    Article  PubMed  CAS  Google Scholar 

  16. Henry YM, Eastell R (2000) Ethnic and gender differences in bone mineral density and bone turnover in young adults: effect of bone size. Osteoporos Int 11:512–517

    Article  PubMed  CAS  Google Scholar 

  17. Miljkovic-Gacic I, Patrick AL, Kammerer CM, Bunker CH (2005) Estimates of African, European and Native American ancestry in Afro-Caribbean men on the island of Tobago. Hum Hered 60:129–133

    Article  PubMed  Google Scholar 

  18. Hill DD, Cauley JA, Sheu Y, Bunker CH, Patrick AL, Baker CE, Beckles GL, Wheeler VW, Zmuda JM (2008) Correlates of bone mineral density in men of African ancestry: the Tobago bone health study. Osteoporos Int 19:227–234

    Article  PubMed  CAS  Google Scholar 

  19. Gundberg CM, Neiman SD, Abrams S, Rosen H (1998) Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–3266

    Article  PubMed  CAS  Google Scholar 

  20. Heath SC, Snow GL, Thompson EA, Tseng C, Wijsman EM (1997) MCMC segregation and linkage analysis. Genet Epidemiol 14:1011–1016

    Article  PubMed  CAS  Google Scholar 

  21. Kosambi D (1944) The estimation of map distances from recombination values. Ann Eugen 12:172–175

    Article  Google Scholar 

  22. Almasy LBJ (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211

    Article  PubMed  CAS  Google Scholar 

  23. Almasy L, Dyer TD, Blangero J (1997) Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet Epidemiol 14:953–958

    Article  PubMed  CAS  Google Scholar 

  24. McKeown NM, Jacques PF, Gundberg CM, Peterson JW, Tucker KL, Kiel DP, Wilson PWF, Booth SL (2002) Dietary and nondietary determinants of vitamin K biochemical measures in men and women. J Nutr 132:1329–1334

    PubMed  CAS  Google Scholar 

  25. Tarallo P, Henny J, Fournier B, Siest G (1990) Plasma osteocalcin: biological variations and reference limits. Scand J Clin Lab Invest 50:649–655

    Article  PubMed  CAS  Google Scholar 

  26. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotmi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753

    Article  PubMed  CAS  Google Scholar 

  27. Lander ES, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  PubMed  CAS  Google Scholar 

  28. Kostenuik PJ (2005) Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 5:618–625

    Article  PubMed  CAS  Google Scholar 

  29. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    Article  PubMed  CAS  Google Scholar 

  30. Xiao G, Jiang D, Gopalakrishnan R, Fanceschi RT (2002) Fibroblast growth factor 2 induction of the osteoclacin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem 277:36181–36187

    Article  PubMed  CAS  Google Scholar 

  31. Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40:198–203

    Article  PubMed  CAS  Google Scholar 

  32. Yakar S, Kim H, Zhao H, Toyoshima Y, Pennisi P, Gavrilova O, Leroith D (2005) The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting. Pediatr Nephrol 20:251–254

    Article  PubMed  Google Scholar 

  33. Guilak F, Leddy HA, Liedtke W (2010) Transient receptor potential vanilloid 4: the sixth sense of the musculoskeletal system? Ann N Y Sci 1192:404–409

    Article  CAS  Google Scholar 

  34. Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, Hyland JC, Körkkö J, Prockop DJ, De Paepe A, Coucke P, Symoens S, Glorieux FH, Roughley PJ, Lund AM, Kuurila-Svahn K, Hartikka H, Cohn DH, Krakow D, Mottes M, Schwarze U, Chen D, Yang K, Kuslich C, Troendle J, Dalgleish R, Byers PH (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutation align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209–221

    Article  PubMed  CAS  Google Scholar 

  35. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 14:203–205

    Article  PubMed  CAS  Google Scholar 

  36. Tran BN, Nguyen ND, Center JR, Eisman JA, Nguyen TV (2009) Enhancement of absolute fracture risk prognosis with genetic marker: the collagen I alpha 1 gene. Calcif Tissue Int 85:379–388

    Article  PubMed  CAS  Google Scholar 

  37. Ioannidis JP, Ng MY, Sham PC, Zintzaras E, Lewis CM, Deng HW, Econs MJ, Karasik D, Devoto M, Kammerer CM, Spector T, Andrew T, Cupples LA, Duncan EL, Foroud T, Kiel DP, Koller D, Langdahl B, Mitchell BD, Peacock M, Recker R, Shen H, Sol-Church K, Spotila LD, Uitterlinden AG, Wilson SG, Kung AW, Ralston SH (2007) Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 22:173–183

    Article  PubMed  CAS  Google Scholar 

  38. Karasik D, Dupuis J, Cho K, Cupples LA, Zhou Y, Kiel DP, Demissie S (2010) Refined QTLs of osteoporosis-related traits by linkage analysis with genome-wide SNPs: Framingham SHARe. Bone 46:1114–1121

    Article  PubMed  CAS  Google Scholar 

  39. Wolf G (2008) Energy regulation by the skeleton. Nutr Rev 66:229–233

    Article  PubMed  Google Scholar 

  40. Hwang YC, Jeong IK, Ahn KJ, Chung HY (2009) The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects. Diabetes Metab Res Rev 25:768–772

    Article  PubMed  CAS  Google Scholar 

  41. Lumanchi F, Camozzi V, Tombolan V, Luisetto G (2009) Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus. Ann N Y Acad Sci 1173(Suppl 1):E64–E67

    Article  Google Scholar 

  42. Foresta C, Strapazzon G, De Toni L, Gianesello L, Calcagno A, Pilon C, Plebani M, Vettor R (2010) Evidence for osteocalcin production by adipose tissue and its role in human metabolism. J Clin Endocrinol Metab. doi:10.2010/jc.2009-2557

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Acknowledgements

This work was supported by grants R03-AR050107 and R01-AR049747 from the NIAMS. Ms. Kuipers was supported by NHLBI grant T32-HL083825.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Epidemiology, A544 Crabtree Hall, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA

    J. M. Zmuda

  2. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA

    A. L. Kuipers, C. S. Nestlerode, C. H. Bunker & A. B. Newman

  3. Department of Orthopaedics and Rehabilitation, Yale School of Medicine, 800 Howard Avenue, New Haven, CT, 06510, USA

    C. Gundberg

  4. Department of Human Genetics, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA

    C. M. Kammerer, A. S. Dressen & J. M. Zmuda

  5. Tobago Health Studies Office, #15 Dutch Fort, Scarborough, Tobago, Trinidad and Tobago

    A. L. Patrick & V. W. Wheeler

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  1. A. L. Kuipers
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  2. C. Gundberg
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  10. J. M. Zmuda
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Correspondence to J. M. Zmuda.

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Kuipers, A.L., Gundberg, C., Kammerer, C.M. et al. Genetic analysis of serum osteocalcin and bone mineral in multigenerational Afro-Caribbean families. Osteoporos Int 23, 1521–1531 (2012). https://doi.org/10.1007/s00198-011-1763-2

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  • DOI: https://doi.org/10.1007/s00198-011-1763-2

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