Abstract
Summary
We evaluated the relationship between a common polymorphism rs1800247 in osteocalcin gene and serum osteocalcin levels, bone mineral density and fracture in Chinese. This was a population-based cross-sectional study. We demonstrated that rs1800247 was associated with bone mineral density and fracture in men and serum osteocalcin levels in women.
Introduction
This study aimed to evaluate the relationship between a common polymorphism rs1800247 in osteocalcin gene and serum total osteocalcin levels, bone mineral density (BMD) and fracture in Chinese middle-aged and elderly men and women.
Methods
This was a population-based cross-sectional study included 5561 individuals aged 45 years or older. Information on fractures sustained after age of 45 were collected. BMD at the lumbar spine, femoral neck and total hip were measured using dual-energy X-ray absorptiometry. The genotyping of rs1800247 was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy.
Results
rs1800247 was associated with lumbar spine BMD and femoral neck BMD in the dominant model adjusted for age, body mass index (BMI), serum total osteocalcin in men (both P = 0.04). Besides, rs1800247 was associated with fracture adjusted for age, BMI, serum total osteocalcin and total hip BMD in the additive and dominant models in men (P = 0.04 and 0.01). In the dominant model, the carriers of CC and TC genotypes was associated with a lower odds of fracture compared with the carriers of TT genotype (OR = 0.60, 95%CI 0.40–0.88, P = 0.01). In men, rs1800247 was not associated with serum total osteocalcin levels in additive, dominant or recessive models. However, rs1800247 was associated with serum total osteocalcin levels in all models adjusted for age, BMI, menopausal status and total hip BMD in women (all p < 0.001), with osteocalcin levels decreasing across TT, TC and CC genotypes. rs1800247 was not associated with BMD or fracture in all models in women.
Conclusions
A common polymorphism rs1800247 in osteocalcin gene may affect the risk of osteoporosis and fracture and serum total osteocalcin levels in Chinese, and there may be gender differences underlying these associations.
Similar content being viewed by others
References
Cummings SR, Melton LJ (2002) Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761–1767
Melton LJ 3rd (2003) Adverse outcomes of osteoporotic fractures in the general population. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 18:1139–1141
Richards JB, Zheng HF, Spector TD (2012) Genetics of osteoporosis from genome-wide association studies: advances and challenges. Nat Rev Genet 13:576–588
Wolf G (1996) Function of the bone protein osteocalcin: definitive evidence. Nutr Rev 54:332–333
Price PA, Parthemore JG, Deftos LJ (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
Ivaska KK, Hentunen TA, Vaaraniemi J, Ylipahkala H, Pettersson K, Vaananen HK (2004) Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. J Biol Chem 279:18361–18369
Emaus N, Nguyen ND, Almaas B, Berntsen GK, Center JR, Christensen M, Gjesdal CG, Grimsgaard AS, Nguyen TV, Salomonsen L, Eisman JA, Fonnebo VM (2013) Serum level of under-carboxylated osteocalcin and bone mineral density in early menopausal Norwegian women. Eur J Nutr 52:49–55
Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD (1994) Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 9:1591–1595
Szulc P, Chapuy MC, Meunier PJ, Delmas PD (1993) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 91:1769–1774
Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamihagi K, Delmas PD (1997) Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab 82:719–724
Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452
Yamada Y, Ando F, Niino N, Shimokata H (2003) Association of polymorphisms of interleukin-6, osteocalcin, and vitamin D receptor genes, alone or in combination, with bone mineral density in community-dwelling Japanese women and men. J Clin Endocrinol Metab 88:3372–3378
Kim JG, Ku SY, Lee DO, Jee BC, Suh CS, Kim SH, Choi YM, Moon SY (2006) Relationship of osteocalcin and matrix Gla protein gene polymorphisms to serum osteocalcin levels and bone mineral density in postmenopausal Korean women. Menopause 13:467–473
Dohi Y, Iki M, Ohgushi H, Gojo S, Tabata S, Kajita E, Nishino H, Yonemasu K (1998) A novel polymorphism in the promoter region for the human osteocalcin gene: the possibility of a correlation with bone mineral density in postmenopausal Japanese women. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 13:1633–1639
Deng HW, Shen H, Xu FH, Deng HY, Conway T, Zhang HT, Recker RR (2002) Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 17:678–686
Gustavsson A, Nordstrom P, Lorentzon R, Lerner UH, Lorentzon M (2000) Osteocalcin gene polymorphism is related to bone density in healthy adolescent females. Osteoporos Int : J Established Result Cooperation Between Eur Found Osteoporos National Osteoporos Found USA 11:847–851
Willing MC, Torner JC, Burns TL, Janz KF, Marshall T, Gilmore J, Deschenes SP, Warren JJ, Levy SM (2003) Gene polymorphisms, bone mineral density and bone mineral content in young children: the Iowa Bone Development Study. Osteoporos Int : J Established Result Cooperation Between Eur Found Osteoporos National Osteoporos Found USA 14:650–658
Chen HY, Tsai HD, Chen WC, Wu JY, Tsai FJ, Tsai CH (2001) Relation of polymorphism in the promotor region for the human osteocalcin gene to bone mineral density and occurrence of osteoporosis in postmenopausal Chinese women in Taiwan. J Clin Lab Anal 15:251–255
Mo XY, Cao CK, Xu FH, Liu MY, Li MX, Qin YJ, Zhou Q, Zhang YY, Deng HW (2004) Lack of association between the HindIII RFLP of the osteocalcin (BGP) gene and bone mineral density (BMD) in healthy pre- and postmenopausal Chinese women. J Bone Miner Metab 22:264–269
Lei SF, Zhang YY, Deng FY, Liu MY, Liu XH, Zhou XG, Deng HW (2005) Bone mineral density and five prominent candidate genes in Chinese men: associations, interaction effects and their implications. Maturitas 51:199–206
Jiang DK, Xu FH, Liu MY, Chen XD, Li MX, Liu YJ, Shen H, Deng HW (2007) No evidence of association of the osteocalcin gene HindIII polymorphism with bone mineral density in Chinese women. J Musculoskelet Neuronal Interact 7:149–154
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 Mineral Res : Off J Am Soc Bone Mineral Res 25:1392–1399
Sowers M, Willing M, Burns T, Deschenes S, Hollis B, Crutchfield M, Jannausch M (1999) Genetic markers, bone mineral density, and serum osteocalcin levels. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 14:1411–1419
Gao X, Hofman A, Hu Y, Lin H, Zhu C, Jeekel J, Jin X, Wang J, Gao J, Yin Y, Zhao N (2010) The Shanghai Changfeng Study: a community-based prospective cohort study of chronic diseases among middle-aged and elderly: objectives and design. Eur J Epidemiol 25:885–893
Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med : J Br Diabet Assoc 15:539–553
Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484
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 Mineral Res : Off J Am Soc Bone Mineral Res 21:1888–1896
Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, Burckhardt P, Cooper C, Christiansen C, Cummings S, Eisman JA, Fujiwara S, Gluer C, Goltzman D, Hans D, Krieg MA, La Croix A, McCloskey E, Mellstrom D, Melton LJ 3rd, Pols H, Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van Staa T, Watts NB, Yoshimura N (2007) The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int : J Established Result Cooperation Between Eur Found Osteoporos National Osteoporos Found USA 18:1033–1046
Kawao N, Kaji H (2015) Interactions between muscle tissues and bone metabolism. J Cell Biochem 116:687–695
Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F, Lejeune H, Kumar TR, Plotton I, Karsenty G (2013) Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Invest 123:2421–2433
Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809
Hannemann A, Breer S, Wallaschofski H, Nauck M, Baumeister SE, Barvencik F, Amling M, Schinke T, Haring R, Keller J (2013) Osteocalcin is associated with testosterone in the general population and selected patients with bone disorders. Andrology 1:469–474
Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T, Sugimoto T (2013) Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int : J Established Result Cooperation Between Eur Found Osteoporos National Osteoporos Found USA 24:1115–1119
Kirmani S, Atkinson EJ, Melton LJ 3rd, Riggs BL, Amin S, Khosla S (2011) Relationship of testosterone and osteocalcin levels during growth. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 26:2212–2216
Lorentzon M, Lorentzon R, Nordstrom 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
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 52:15–18
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
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
Kuipers AL, Gundberg C, Kammerer CM, Dressen AS, Nestlerode CS, Patrick AL, Wheeler VW, Bunker CH, Newman AB, Zmuda JM (2012) Genetic analysis of serum osteocalcin and bone mineral in multigenerational Afro-Caribbean families. Osteoporos Int : J Established Result Cooperation Between Eur Found Osteoporos National Osteoporos Found USA 23:1521–1531
Seeman E (2001) Clinical review 137: sexual dimorphism in skeletal size, density, and strength. The Journal of Clinical Endocrinology and Metabolism 86:4576–4584
Orwoll ES, Belknap JK, Klein RF (2001) Gender specificity in the genetic determinants of peak bone mass. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 16:1962–1971
Turner CH, Sun Q, Schriefer J, Pitner N, Price R, Bouxsein ML, Rosen CJ, Donahue LR, Shultz KL, Beamer WG (2003) Congenic mice reveal sex-specific genetic regulation of femoral structure and strength. Calcif Tissue Int 73:297–303
Naganathan V, Macgregor A, Snieder H, Nguyen T, Spector T, Sambrook P (2002) Gender differences in the genetic factors responsible for variation in bone density and ultrasound. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 17:725–733
Karasik D, Cupples LA, Hannan MT, Kiel DP (2003) Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study. Bone 33:308–316
Duncan EL, Cardon LR, Sinsheimer JS, Wass JA, Brown MA (2003) Site and gender specificity of inheritance of bone mineral density. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 18:1531–1538
Acknowledgments
This study was supported by the following grants: the National Key Basic Research Program of China (Grant No. 2012CB524906 to Xin Gao and Grant No. 2011CB504004 to Xin Gao; http://www.973.gov.cn/Default_3.aspx), the Major Project of Shanghai Bureau of Health (Grant No. 12GWZX0103 and Grant No. 13ZYJB0802 to Xin Gao), and the Project of Shanghai Bureau of Health (Grant No. 20124242 to Yan Ling).
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ling, Y., Gao, X., Lin, H. et al. A common polymorphism rs1800247 in osteocalcin gene was associated with serum osteocalcin levels, bone mineral density, and fracture: the Shanghai Changfeng Study. Osteoporos Int 27, 769–779 (2016). https://doi.org/10.1007/s00198-015-3244-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-015-3244-5