Abstract
Introduction
Peak bone mineral density (BMD) achieved during adulthood is a major determinant of osteoporotic fracture in later life. Although environmental factors affect peak BMD, it is a highly heritable trait. Recently, bone morphogenetic protein 2 (BMP2) was reported as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations.
Methods
To determine whether polymorphisms in the BMP2 gene contribute to BMD variation in our population of healthy American whites, we tested seven single nucleotide polymorphisms (SNPs), four of which were associated with osteoporotic phenotypes in the previous study. BMD at the femoral neck and lumbar spine (L2–L4) were measured by dual energy X-ray absorptiometry (DXA) in 411 men (age 18–61) and 1,291 pre-menopausal women (age 20–50). SNP genotypes/haplotypes were tested for population-based association with BMD using analysis of variance.
Results
None of the polymorphisms tested reached statistical significance (all p values >0.05) for BMD at the femoral neck or lumbar spine in either gender. Two of the SNP haplotypes spanning the entire BMP2 gene were marginally associated with BMD in men (p values=0.019−0.043). However, these haplotypes would account for only a small, if any, portion of BMD variation and would not be significant after adjustment for multiple comparisons.
Conclusions
These results demonstrate that genetic variations in BMP2 do not substantially contribute to BMD variation in our population of healthy American whites.
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References
Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326
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 1:1–10
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534
Wang EA, Rosen V, D’Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P,Luxenberg DP, McQuaid D, Moutsatsos IK, Nove J, Wozney JM (1990) Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A 87:2220–2224
Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T, Rosen V, Wozney JM, Fujisawa–Sehara A, Suda T (1994) Bone morphogenetic protein–2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127:1755–1766
Thies RS, Bauduy M, Ashton BA, Kurtzberg L, Wozney JM, Rosen V (1992) Recombinant human bone morphogenetic protein–2 induces osteoblastic differentiation in W–20–17 stromal cells. Endocrinology 130:1318–1324
Yamaguchi A, Katagiri T, Ikeda T, Wozney JM, Rosen V, Wang EA, Kahn AJ, Suda T, Yoshiki S (1991) Recombinant human bone morphogenetic protein–2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. J Cell Biol 113:681–687
Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337
Abecasis GR, Cookson WOC (2000) GOLD–graphical overview of linkage disequilibrium. Bioinformatics 16:182–183
Abecasis GR, Cardon LR, Cookson WOC (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292
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 85:3116–3120
Peacock M, Koller DL, Hui S, Johnston CC, Foroud T, Econs MJ (2004) Peak bone mineral density at the hip is linked to chromosomes 14q and 15q. Osteoporos Int 15:489–496
Koller DL, Peacock M, Lai D, Foroud T, Econs MJ (2004) False positive rates in association studies as a function of degree of stratification. J Bone Miner Res 19:1291–1295
Acknowledgements
We thank siblings and their parents who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants P01 AG–18397, R01 AR–43476, M01 RR–00750, and K24 AR–02095. SNP genotyping by MALDI-TOF mass spectrometry used the facilities of the Center for Medical Genomics at Indiana University School of Medicine, which is supported in part by a grant from the Indiana Genomics Initiative (INGEN). INGEN is supported in part by the Lilly Endowment, Inc. We thank Jinghua Zhao and Gayathri Rajan at the Center for Medical Genomics for their technical support on SNP genotyping.
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Ichikawa, S., Johnson, M.L., Koller, D.L. et al. Polymorphisms in the bone morphogenetic protein 2 (BMP2) gene do not affect bone mineral density in white men or women. Osteoporos Int 17, 587–592 (2006). https://doi.org/10.1007/s00198-005-0018-5
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DOI: https://doi.org/10.1007/s00198-005-0018-5