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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2005

Open Access 01-12-2005 | Research article

Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel

Authors: Peter Tzakas, Betty YL Wong, Alexander G Logan, Laurence A Rubin, David EC Cole

Published in: BMC Musculoskeletal Disorders | Issue 1/2005

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Abstract

Background

Variance of peak bone mass has a substantial genetic component, as has been shown with twin studies examining quantitative measures such as bone mineral density (BMD) and quantitative ultrasound (QUS). Evidence implicating single nucleotide polymorphisms (SNPs) of the transforming growth factor beta-1 (TGFB1) gene is steadily accumulating. However, a comprehensive look at multiple SNPs at this locus for their association with indices of peak bone mass has not been reported.

Methods

A cohort of 653 healthy Caucasian females 18 to 35 years old was genotyped for seven TGFB1 SNPs. Polymorphisms were detected by restriction endonuclease digestion of amplified DNA segments.

Results

The frequencies of the least common allele at G-800A, C-509T, codon 10 (L10P), codon 25 (R25P), codon 263 (T263I), C861-20T, and 713-8 delC loci were 0.07, 0.33, 0.41, 0.08, 0.04, 0.25 and 0.01, respectively. A significant association was seen between QUS Stiffness Index (QUS-SI) and the SNP at codon 10 and the linked promoter SNP, C-509T. This association remained significant after multiple regression was used to incorporate important clinical covariates – age, BMI, level of activity, family history, and caffeine intake – into the model.

Conclusion

The association of QUS-SI with -509T is consistent with a gene-dose effect, while only individuals homozygous for the codon 10P allele showed a significant increase. In this cohort of young healthy Caucasian females, the T allele at position -509 is associated with greater bone mass as measured by calcaneal ultrasound.
Appendix
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Literature
1.
Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults. A twin study. J Clin Invest. 1987, 80: 706-710.CrossRefPubMedPubMedCentral
2.
Patel MS, Rubin LA, Cole DE: Genetic determinants of peak bone mass. The Osteoporosis Primer. Edited by: Henderson JE, Goltzman D. 2000, Cambridge: Cambridge University Press, 131-146.CrossRef
3.
Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA: Prediction of bone density from vitamin D receptor alleles. Nature. 1994, 367: 284-287. 10.1038/367284a0.CrossRefPubMed
4.
Rubin LA, Hawker GA, Peltekova VD, Fielding LJ, Ridout R, Cole DE: Determinants of peak bone mass: clinical and genetic analyses in a young female Canadian cohort. J Bone Miner Res. 1999, 14: 633-643.CrossRefPubMed
5.
Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H: Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res. 1996, 11: 306-311.CrossRefPubMed
6.
Patel MS, Cole DE, Smith JD, Hawker GA, Wong B, Trang H, Vieth R, Meltzer P, Rubin LA: Alleles of the estrogen receptor alpha-gene and an estrogen receptor cotranscriptional activator gene, amplified in breast cancer-1 (AIB1), are associated with quantitative calcaneal ultrasound. J Bone Miner Res. 2000, 15: 2231-2239.CrossRefPubMed
7.
Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH: Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet. 1996, 14: 203-205. 10.1038/ng1096-203.CrossRefPubMed
8.
Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, Kaneki M, Ouchi Y: Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res. 1997, 12: 1438-1445.CrossRefPubMed
9.
Yamada Y, Miyauchi A, Goto J, Takagi Y, Okuizumi H, Kanematsu M, Hase M, Takai H, Harada A, Ikeda K: Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998, 13: 1569-1576.CrossRefPubMed
10.
Seyedin SM, Thompson AY, Bentz H, Rosen DM, McPherson JM, Conti A, Siegel NR, Galluppi GR, Piez KA: Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986, 261: 5693-5695.PubMed
11.
Cohen MM: TGF beta/Smad signaling system and its pathologic correlates. Am J Med Genet A. 2003, 116: 1-10. 10.1002/ajmg.a.10750.CrossRef
12.
Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van ML, Vanhoenacker F, Verbruggen L: Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000, 26: 273-275. 10.1038/81563.CrossRefPubMed
13.
Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S: TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004, 127: 104-107. 10.1002/ajmg.a.20671.CrossRef
14.
Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ: Defective hematopoiesis and vasculogenesis in transforming growth-factor-beta-1 knock out mice. Development. 1995, 121: 1845-1854.PubMed
15.
Derynck R, Jarrett JA, Chen EY, Goeddel DV: The murine transforming growth factor-beta precursor. J Biol Chem. 1986, 261: 4377-4379.PubMed
16.
Cambien F, Ricard S, Troesch A, Mallet C, Generenaz L, Evans A, Arveiler D, Luc G, Ruidavets JB, Poirier O: Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study. Hypertension. 1996, 28: 881-887.CrossRefPubMed
17.
Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen EF: A sequence variation: 713-8delC in the transforming growth factor-beta 1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone. 1997, 20: 289-294. 10.1016/S8756-3282(96)00363-8.CrossRefPubMed
18.
Keen RW, Snieder H, Molloy H, Daniels J, Chiano M, Gibson F, Fairbairn L, Smith P, MacGregor AJ, Gewert D: Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta 1 gene and hip bone mineral density: a study of female twins. Rheumatology (Oxford). 2001, 40: 48-54. 10.1093/rheumatology/40.1.48.CrossRef
19.
Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD: Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet. 1999, 8: 93-97. 10.1093/hmg/8.1.93.CrossRefPubMed
20.
Lau HH, Ho AY, Luk KD, Kung AW: Transforming growth factor-beta1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in southern chinese women. Calcif Tissue Int. 2004, 74: 516-521. 10.1007/s00223-004-0163-4.CrossRefPubMed
21.
Yamada Y, Miyauchi A, Takagi Y, Tanaka M, Mizuno M, Harada A: Association of the C-509-->T polymorphism, alone of in combination with the T869-->C polymorphism, of the transforming growth factor-beta1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J Mol Med. 2001, 79: 149-156. 10.1007/s001090100190.CrossRefPubMed
22.
Hinke V, Seck T, Clanget C, Scheidt-Nave C, Ziegler R, Pfeilschifter J: Association of transforming growth factor-beta1 (TGFbeta1) T29 -> C gene polymorphism with bone mineral density (BMD), changes in BMD, and serum concentrations of TGF-beta1 in a population-based sample of postmenopausal german women. Calcif Tissue Int. 2001, 69: 315-320. 10.1007/s002230020024.CrossRefPubMed
23.
Dick IM, Devine A, Li S, Dhaliwal SS, Prince RL: The T869C TGF beta polymorphism is associated with fracture, bone mineral density, and calcaneal quantitative ultrasound in elderly women. Bone. 2003, 33: 335-341. 10.1016/S8756-3282(03)00158-3.CrossRefPubMed
24.
Bertoldo F, D'Agruma L, Furlan F, Colapietro F, Lorenzi MT, Maiorano N, Iolascon A, Zelante L, Locascio V, Gasparini P: Transforming growth factor-beta1 gene polymorphism, bone turnover, and bone mass in Italian postmenopausal women. J Bone Miner Res. 2000, 15: 634-639.CrossRefPubMed
25.
Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF: Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis. Bone. 2003, 32: 297-310. 10.1016/S8756-3282(02)00971-7.CrossRefPubMed
26.
Ziv E, Kahn A, Cauley J, Morin P, Saiz R, Browner W: No association between the TGF-beta 1 Leu10Pro polymorphism and osteoporosis among white women in the United States. Am J Med. 2003, 114: 227-231. 10.1016/S0002-9343(02)01393-1.CrossRefPubMed
27.
Yamada Y, Hosoi T, Makimoto F, Tanaka H, Seino Y, Ikeda K: Transforming growth factor beta-1 gene polymorphism and bone mineral density in Japanese adolescents. Am J Med. 1999, 106: 477-479. 10.1016/S0002-9343(99)00043-1.CrossRefPubMed
28.
Sawitzke AD, Sawitzke AL, Ward RH: HLA-DPB typing using co-digestion of amplified fragments allows efficient identification of heterozygous genotypes. Tissue Antigens. 1992, 40: 175-181.CrossRefPubMed
29.
Peltekova VD, Cole DE, Pavlova A, Rubin LA: Improved method for direct haplotyping at the vitamin D receptor gene locus. Clin Biochem. 1998, 31: 191-194. 10.1016/S0009-9120(98)00005-8.CrossRefPubMed
30.
Weir BS: . Genetic Data Analysis II. 1996, Sunderland, Massachusetts: Sinauer Associates, Inc. Publishers
31.
Hamilton DC, Cole DE: Standardizing a composite measure of linkage disequilibrium. Ann Hum Genet. 2004, 68: 234-239. 10.1046/j.1529-8817.2004.00056.x.CrossRefPubMed
32.
Pfeilschifter J, Seyedin SM, Mundy GR: Transforming growth factor beta inhibits bone resorption in fetal rat long bone cultures. J Clin Invest. 1988, 82: 680-685.CrossRefPubMedPubMedCentral
33.
Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ: A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci. 2000, 113 (Pt 13): 2445-2453.PubMed
34.
Antosz ME, Bellows CG, Aubin JE: Effects of transforming growth factor beta and epidermal growth factor on cell proliferation and the formation of bone nodules in isolated fetal rat calvaria cells. J Cell Physiol. 1989, 140: 386-395. 10.1002/jcp.1041400225.CrossRefPubMed
35.
Dieudonne SC, Semeins CM, Goei SW, Vukicevic S, Nulend JK, Sampath TK, Helder M, Burger EH: Opposite effects of osteogenic protein and transforming growth factor beta on chondrogenesis in cultured long bone rudiments. J Bone Miner Res. 1994, 9: 771-780.CrossRefPubMed
36.
Syrris P, Carter ND, Metcalfe JC, Kemp PR, Grainger DJ, Kaski JC, Crossman DC, Francis SE, Gunn J, Jeffery S: Transforming growth factor-beta1 gene polymorphisms and coronary artery disease. Clin Sci. 1998, 95: 659-667. 10.1042/CS19980154.CrossRefPubMed
37.
Luedecking EK, DeKosky ST, Mehdi H, Ganguli M, Kamboh MI: Analysis of genetic polymorphisms in the transforming growth factor-beta1 gene and the risk of Alzheimer's disease. Hum Genet. 2000, 106: 565-569. 10.1007/s004390050026.CrossRefPubMed
38.
Walter P, Johnson AE: Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Annu Rev Cell Biol. 1994, 10: 87-119. 10.1146/annurev.cb.10.110194.000511.CrossRefPubMed
39.
Awad MR, El Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV: Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998, 66: 1014-1020. 10.1097/00007890-199810270-00009.CrossRefPubMed
40.
Yamada Y: Association of polymorphisms of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis. Pharmacogenetics. 2001, 11: 765-771. 10.1097/00008571-200112000-00004.CrossRefPubMed
41.
Njeh CF, Boivin CM, Langton CM: The role of ultrasound in the assessment of osteoporosis: a review. Osteoporos Int. 1997, 7: 7-22. 10.1007/BF01623454.CrossRefPubMed
42.
Howard GM, Nguyen TV, Harris M, Kelly PJ, Eisman JA: Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res. 1998, 13: 1318-1327.CrossRefPubMed
43.
Beamer WG, Donahue LR, Rosen CJ, Baylink DJ: Genetic variability in adult bone density among inbred strains of mice. Bone. 1996, 18: 397-403. 10.1016/8756-3282(96)00047-6.CrossRefPubMed
44.
Chakravarti A: Population genetics--making sense out of sequence. Nat Genet. 1999, 21: 56-60. 10.1038/4482.CrossRefPubMed
Metadata
Title
Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel
Authors
Peter Tzakas
Betty YL Wong
Alexander G Logan
Laurence A Rubin
David EC Cole
Publication date
01-12-2005
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2005
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-6-29

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