Calcified Tissue International

, Volume 76, Issue 2, pp 107–112 | Cite as

The −1997 G/T Polymorphism in the COLIA1 Upstream Regulatory Region is Associated with Hip Bone Mineral Density (BMD) in Chinese Nuclear Families

  • Yuan-Yuan Zhang
  • Shu-Feng Lei
  • Xiao-Yang Mo
  • Yan-Bo  Wang
  • Miao-Xin Li
  • Hong-Wen Deng


Type I collagen is the most abundant protein of bone matrix, and the collagen type I alpha 1(COLIA1) gene has been considered one of the most important candidate genes for osteoporosis. In this study, we simultaneously tested linkage and/or association of the −1997 G/T polymorphism in the COLIA1 upstream regulatory region with the variation of bone mineral density (BMD) in 1263 subjects from 402 Chinese nuclear families, consisted of both parents and at least one healthy female offspring from 20 to 45 years of age. All the subjects were genotyped by using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). BMD of the lumbar spine (L1–L4) and hip (respective and combined phenotype of the femoral neck, trochanter, and intertrochanter) was measured by dual-energy X-ray absorptiometry (DXA). By using the tests implemented in program QTDT (quantitative transmission disequilibrium test), we found significant within-family association (via TDT) between the −1997 G/T polymorphism with BMD variation at all the hip sites (respective and combined phenotypes, P < 0.05). The amount of BMD variation explained by the −1997G/T polymorphism was 1.6%, 2.0%, 1.2%, and 1.3% at the total hip, femoral neck, trochanter, and intertrochanter, respectively. Because of the limited number of sib pairs in this sample, we did not find evidence of linkage. In summary, the −1997 G/T polymorphism in the COLIA1 gene is likely to be in linkage disequilibrium with a nearby functional polymorphism affecting hip BMD, or the -1997 G/T polymorphism itself may have an important effect on the variation of hip BMD in our Chinese sample.


Association Linkage COLIA1 gene Bone mineral density (BMD) Osteoporosis 



We thank Ms Yuan-Juan Qin, Qi Zhou, and Qi-Ren Huang for their efforts with sample recruitment. The study was partially supported by a key project grant from National Science Foundation of China (NSFC) (3023021); an Outstanding Young Scientist Grant, a project from NSFC (30025025); and a project from Scientific Research Fund of Hunan Provincial Education Department (02A027). Two investigators (H.W.D. and Y.Y.Z.) were partially supported by grants from Health Future Foundation, NIH, State of Nebraska (LB 692 and 595).


  1. 1.
    Kanis, A, Melton, III LJ, Christiansen, C, Johnston, CC, Khaltaev, N 1994The diagnosis of osteoporosisJ Bone Miner Res911371141PubMedGoogle Scholar
  2. 2.
    Xu, SZ, Zhou, W, Mao, XD, Xu, J, Xu, LP, Ren, JY 2001Reference data and predictive diagnostic models for calcaneus bone mineral density measured with single-energy X-ray absorptiometry in 7428 ChineseOsteoporos Int12755762CrossRefPubMedGoogle Scholar
  3. 3.
    Liu, Z, Piao, J, Pang, L, Qing, X, Nan, S, Pan, Z, Guo, Y, Li, F, Wang, X, Liu, J, Chen, X 2002The diagnostic criteria for primary osteoporosis and the incidence of osteoporosis in ChinaJ Bone Miner Metab4181189CrossRefGoogle Scholar
  4. 4.
    Cooper, C, Campion, G, Melton, LJ 1992Hip fractures in the elderly: A world-wide projectionOsteoporos Int2285289PubMedGoogle Scholar
  5. 5.
    Suzuki, T 2001Risk factors for osteoporosis in AsiaJ Bone Miner Metab3133141CrossRefGoogle Scholar
  6. 6.
    Cummings, SR, Kelsey, JL, Nevitt, MC, O’Dowd, KJ 1985Epidemiology of osteoporosis and osteoporotic fracturesEpidemiol Rev7178208PubMedGoogle Scholar
  7. 7.
    Melton, LJ, Kan, SH, Frye, MA, Wahner, HW, O’Fallon, WM, Riggs, BL 1989Epidemiology of vertebral fractures in womenAm J Epidemiol12910001011PubMedGoogle Scholar
  8. 8.
    Deng, HW, Chen, WM, Recker, S, Stegman, MR, Li, JL, Davies, KM, Zhou, Y, Deng, HY, Heaney, R, Recker, RR 2000Genetic determination of Colles’ fractures and differential bone mass in women with and without Colles’ fracturesJ Bone Miner Res1512431252PubMedGoogle Scholar
  9. 9.
    Dequeker, J, Nijs, J, Verstraeten, A, Geusens, P, Gevers, G 1987Genetic determinants of bone mineral content at the spine and radius: A twin studyBone8207209CrossRefPubMedGoogle Scholar
  10. 10.
    Slemenda, CW, Christian, JC, Williams, CJ, Norton, JA, Johnston, CC,Jr. 1991Genetic determinants of bone mass in adult woman: A revaluation of the twin model and the potential importance of gene interaction on heritability estimatesJ Bone Miner Res6561567PubMedGoogle Scholar
  11. 11.
    Sowers, MR, Boehnke, M, Jannausch, ML, Crutchfield, M, Corton, G, Burns, BT 1992Familiality and partitioning the variability of femoral bone mineral density in women of child-bearing ageCalcif Tissue Int50110114CrossRefPubMedGoogle Scholar
  12. 12.
    Gueguen, R, Jouanny, P, Guillemin, F, Kuntz, C, Pourel, J, Siest, G 1995Segregation analysis and variance components analysis of bone mineral density in health familiesJ Bone Miner Res1020172022PubMedGoogle Scholar
  13. 13.
    Deng, HW, Stegman, MR, Davies, KM, Conway, T, Recker, RR 1999Genetic determination of variation and covariation of peak bone mass at the hip and spineJ Clin Densitom2251263CrossRefPubMedGoogle Scholar
  14. 14.
    Deng, HW, Chen, WM, Conway, T, Zhou, Y, Davies, KM, Stegman, MR, Deng, HY, Recker, RR 2000Determination of bone mineral density of the hip and spine in human pedigrees by genetic and life-style factorsGenet Epidemiol19160177CrossRefPubMedGoogle Scholar
  15. 15.
    Morrison, NA, Qi, JC, Tokita, A, Kelly, PJ, Crofts, L, Nguyen, TV, Sambrook, PN, Eisman, JA 1994Prediction of bone density from vitamin D receptor allelesNature367284287CrossRefPubMedGoogle Scholar
  16. 16.
    Tokita, A, Matsumoto, H, Morrison, NA, Tawa, T, Miura, Y, Fukamauchi, K, Mitsuhashi, N, Irimoto, M, Yamamori, S, Miura, M, Watanable, T, Kuwabara, Y, Yabuta, K, Eisman, JA 1996Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese womenJ Bone Miner Res1110031009PubMedGoogle Scholar
  17. 17.
    Zhang, YY, Long, JR, Liu, PY, Liu, YJ, Shen, H, Zhao, LJ, Deng, HW 2003Estrogen receptor α and vitamin D receptor gene polymorphisms and bone mineral density: Association study of healthy pre- and post-menopausal Chinese womenBiochem Biophys Res Commun308777783CrossRefPubMedGoogle Scholar
  18. 18.
    Kobayashi, S, Inoue, S, Hosoi, T, Ouchi, Y, Shiraki, M, Orimo, H 1996Association of bone mineral density with polymorphism of the estrogen receptor geneJ Bone Miner Res11306311PubMedGoogle Scholar
  19. 19.
    Murray, RE, McGuigan, F, Grant, SF, Reid, DM, Ralston, SH 1997Polymorphisms of the interleukin-6 gene are associated with bone mineral densityBone218992CrossRefPubMedGoogle Scholar
  20. 20.
    Garnero, P, Borel, O, Sornay-Rendu, E, Delmas, PD 1995Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy premenopausal womenJ Bone Miner Res1012831288PubMedGoogle Scholar
  21. 21.
    Garnero, P, Borel, O, Sornay-Rendu, E, Arlot, ME, Delmas, PD 1996Vitamin D receptor gene polymorphisms are not related to bone turnover, rate of bone loss and bone mass in postmenopausal women: The OFELY studyJ Bone Miner Res11827834PubMedGoogle Scholar
  22. 22.
    Spotila, LD, Caminis, J, Johnston, R, Shimoya, KS, O’Connor, MPO, Prockop, DJ 1996Vitamin D receptor genotype is not associated with bone mineral density in three ethnic/regional groupsCalcif Tissue Int59235237CrossRefPubMedGoogle Scholar
  23. 23.
    Han, KO, Moon, IG, Kang, YS, Chuang, HY, Min, HK, Han, IK 1997Nonassociation of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean postmenopausal womenJ Clin Endocrinol Metab82991995CrossRefPubMedGoogle Scholar
  24. 24.
    Sykes B,  Human genetics1990Bone disease cracks geneticsNature3481820CrossRefPubMedGoogle Scholar
  25. 25.
    Uitterlinden, AG, Burger, H, Huang, Q, Yue, F, McGuigan, FE, Grant, SF, Hofman, A, Leeuwen, JPV, Pols, HA, Ralston, SH 1998Relation of alleles of the collagen type I alpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal womenN Engl J Med33810161021CrossRefPubMedGoogle Scholar
  26. 26.
    Weichetova, M, Stepan, JJ, Michalska, D, Haas, T, Pols, HA, Uitterlinden, AG 2000COLIA1 polymorphism contributes to bone mineral density to assess prevalent wrist fracturesBone26287290CrossRefPubMedGoogle Scholar
  27. 27.
    Heegaard, A, Jorgensen, HL, Vestergaard, AW, Hassager, C, Ralston, SH 2000Lack of influence of collagen type I alpha1 Sp1 binding site polymorphism on the rate of bone loss in a cohort of postmenopausal Danish women followed for 18 yearsCalcif Tissue Int66409413CrossRefPubMedGoogle Scholar
  28. 28.
    Liden, M, Wilen, B, Ljunghall, S, Melhus, H 1998Polymorphism at the Sp1 binding site in the collagen type I alpha 1 gene does not predict bone mineral density in postmenopausal women in SwedenCalcif Tissue Int63293295CrossRefPubMedGoogle Scholar
  29. 29.
    Garnero, P, Borel, O, Grant, SF, Ralston, SH, Delmas, PD 1998Collagen I alpha1 Sp1 polymorphism, bone mass, and bone turnover in healthy French premenopausal women: The OFELY studyJ Bone Miner Res13813817PubMedGoogle Scholar
  30. 30.
    Grant, F, Reid, DM, Blake, G, Herd, R, Fogelman, I, Ralston, SH 1996Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 geneNat Genet14203205CrossRefPubMedGoogle Scholar
  31. 31.
    Mann, V, Ralston, SH 2003Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fractureBone32711717CrossRefPubMedGoogle Scholar
  32. 32.
    Mann, V, Hobson, EE, Li, B, Stewart, TL, Grant, SF, Robins, SP, Aspden, RM, Ralston, SH 2001A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and qualityJ Clin Invest107899907PubMedGoogle Scholar
  33. 33.
    Lei, SF, Deng, FY, Liu, XH, Huang, QR, Qin, YJ, Zhou, Q, Jiang, DK, Li, YM, Mo, XY, Liu, MY, Chen, XD, Wu, XS, Shen, H, Dvornyk, V, Zhao, LJ, Recker, RR, Deng, HW 2003Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicityJ Bone Miner Metab213442CrossRefPubMedGoogle Scholar
  34. 34.
    Garcia-Giralt, N, Nogués, X, Enjuanes, A, Puig, J, Mellibovsky, L, Bay-jensen, A, Carreras, R, Balcells, S, Díez-pérez, A, Grinberg, A 2002Two new single-nucleotide polymorphism in the COL1A1 upstream regulatory region and their relationship to bone mineral densityJ Bone Miner Res17384393PubMedGoogle Scholar
  35. 35.
    Deng, HW, Shen, H, Xu, FH, Deng, HY, Conway, T, Zhang, HT, Recker, RR 2002Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral densityJ Bone Miner Res17678686PubMedGoogle Scholar
  36. 36.
    Lu, SD 1999Current protocols for molecular biology (in Chinese)2Xiehe Medical University Press .6193Google Scholar
  37. 37.
    Fulker, DW, Cherny, SS, Sham, PC, Hewitt, JK 1999Combined linkage and association analysis for quantitative traitsAm J Hum Genet64259267CrossRefPubMedGoogle Scholar
  38. 38.
    Abecasis, GR, Cookson, WO, Cardon, LR 2000A general test of association for quantitative traits in nuclear familiesAm J Hum Genet66279292CrossRefPubMedGoogle Scholar
  39. 39.
    Abecasis, GR, Cookson, WO, Cardon, LR 2000Pedigree tests of transmission disequilibriumEur J Hum Genet8545551CrossRefPubMedGoogle Scholar
  40. 40.
    Lei, SF, Deng, FY, Li, MX, Dvornyk, V, Deng, HW 2004Bone mineral density in elderly Chinese: effects of age, sex, weight, height, and body mass indexJ Bone Miner Metab227178CrossRefPubMedGoogle Scholar
  41. 41.
    Yao, WJ, Wu, CH, Wang, ST, Chang, CJ, Chiu, NT, Yu, CY 2001Differential changes in regional bone mineral density in healthy Chinese: age-related and sex-dependentCalcif Tissue Int68330336CrossRefPubMedGoogle Scholar
  42. 42.
    Deng, HW, Li, J, Recker, RR 2001Effect of polygenes on Xiong’s transmission disequilibrium test of a QTL in nuclear families with multiple childrenGenet Epidemiol21243265CrossRefPubMedGoogle Scholar
  43. 43.
    Deng, HW, Li, J 2002The effects of selected sampling on the transmission disequilibrium test of a quantitative trait locusGenet Res79161174CrossRefPubMedGoogle Scholar
  44. 44.
    Liu, YZ, Liu, YJ, Recker, RR, Deng, HW 2003Molecular studies of gene identification for osteoporosis: the 2002 updateJ Endocrinol177147196CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Yuan-Yuan Zhang
    • 1
    • 2
  • Shu-Feng Lei
    • 1
  • Xiao-Yang Mo
    • 1
  • Yan-Bo  Wang
    • 1
  • Miao-Xin Li
    • 1
  • Hong-Wen Deng
    • 1
    • 2
    • 3
  1. 1.Laboratory of Molecular and Statistical GeneticsCollege of Life Sciences, Hunan Normal UniversityChangshaP. R. China
  2. 2.Osteoporosis Research Center and Department of Biomedical SciencesCreighton UniversityOmahaUSA
  3. 3.The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Sciences and TechnologyXi’an Jiaotong UniversityXi’anP. R. China

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