Calcified Tissue International

, Volume 84, Issue 2, pp 85–96 | Cite as

Haplotypes of Promoter and Intron 1 Polymorphisms in the COLIA1 Gene Are Associated with Increased Risk of Osteoporosis

  • L. B. Husted
  • T. Harsløf
  • N. Gonzalez-Bofill
  • A. Schmitz
  • M. Carstens
  • L. Stenkjær
  • B. L. Langdahl


Osteoporosis is a common age-related disease with a strong genetic influence. COLIA1 is one of the most extensively studied candidate genes and has consistently been associated with BMD and fracture. We examined the effects of the polymorphisms –1997G>T, –1663indelT, and +1245G>T and their haplotypes on vertebral fractures and bone mineral density (BMD) in a case-control study comprising 462 osteoporotic patients and 336 controls. The −1663indelT polymorphism was associated with a decreased lumbar spine (ls) BMD, 0.75 ± 0.14 g/cm2, in individuals with the del/del genotype versus 0.83 ± 0.18 and 0.85 ± 0.18 g/cm2 in individuals with the ins/del and ins/ins genotypes, respectively (p = 0.02). The T-allele of the +1245G>T polymorphism, which was in strong linkage disequilibrium (LD) with –1663indelT, was also associated with a decreased lsBMD (p = 0.02). –1997G>T was not significantly associated with lsBMD. The three most common haplotypes accounted for 98.5% of the alleles. Individuals with one or two copies of haplotype 1 (–1997G/–1663ins/+1245G) had a significantly higher lsBMD, 0.84 ± 0.18 and 0.85 ± 0.15 g/cm2, respectively, versus 0.78 ± 0.15 g/cm2 in noncarriers (p = 0.01). Individuals with two copies of haplotype 2 (–1997G/–1663del/+1245T) had a significantly lower lsBMD, 0.76 ± 0.14 g/cm2, versus 0.85 ± 0.18 and 0.82 ± 0.18 g/cm2, respectively, in individuals with zero or one copy (p = 0.03). The odds ratio for vertebral fracture in individuals carrying the variant T-allele of the –1997G>T polymorphism was 1.49 (CI, 1.03–2.16; p = 0.03). Logistic regression revealed that this effect was partly independent of BMD. In conclusion, the −1663del and +1245T alleles influence BMD negatively, whereas the –1997T-allele has a minor effect on BMD but increases the risk of vertebral fractures. These findings are in agreement with functional studies showing that these polymorphisms influence gene expression.


Collagen Fracture risk BMD Polymorphisms 


  1. 1.
    Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O’Fallon WM, Riggs BL (1990) Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res 5:311–319PubMedGoogle Scholar
  2. 2.
    Pocock NA, Eisman JA, Yeates MG, Sambrook PN, Eberl S (1986) Physical fitness is a major determinant of femoral neck and lumbar spine bone mineral density. J Clin Invest 78:618–621PubMedCrossRefGoogle Scholar
  3. 3.
    Hermann AP, Brot C, Gram J, Kolthoff N, Mosekilde L (2000) Premenopausal smoking and bone density in 2015 perimenopausal women. J Bone Miner Res 15:780–787PubMedCrossRefGoogle Scholar
  4. 4.
    Huuskonen J, Vaisanen SB, Kroger H, Jurvelin C, Bouchard C, Alhava E, Rauramaa R (2000) Determinants of bone mineral density in middle aged men: a population-based study. Osteoporos Int 11:702–708PubMedCrossRefGoogle Scholar
  5. 5.
    Uitterlinden AG, Pols HA, Burger H, Huang Q, van Daele PL, Van Duijn CM, Hofman A, Birkenhager JC, van Leeuwen JP (1996) A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 11:1241–1248PubMedGoogle Scholar
  6. 6.
    Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114PubMedCrossRefGoogle Scholar
  7. 7.
    Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen EF (1997) 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 20:289–294PubMedCrossRefGoogle Scholar
  8. 8.
    Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Perez CR, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP (2008) Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42:969–981PubMedCrossRefGoogle Scholar
  9. 9.
    Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Reeve J, Reid DM, Amedei A, Bassiti A, Bustamante M, Husted LB, ez-Perez A, Dobnig H, Dunning AM, Enjuanes A, Fahrleitner-Pammer A, Fang Y, Karczmarewicz E, Kruk M, van Leeuwen JP, Mavilia C, van Meurs JB, Mangion J, McGuigan FE, Pols HA, Renner W, Rivadeneira F, van Schoor NM, Scollen S, Sherlock RE, Ioannidis JP (2006) The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med 145:255–264PubMedGoogle Scholar
  10. 10.
    Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114PubMedCrossRefGoogle Scholar
  11. 11.
    Byers PH (1990) Brittle bones—fragile molecules: disorders of collagen gene structure and expression. Trends Genet 6:293–300PubMedCrossRefGoogle Scholar
  12. 12.
    Rauch F, Glorieux FH (2004) Osteogenesis imperfecta. Lancet 363(9418):1377–1385PubMedCrossRefGoogle Scholar
  13. 13.
    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. Nature Genet 14:203–205PubMedCrossRefGoogle Scholar
  14. 14.
    Langdahl BL, Ralston SH, Grant SF, Eriksen EF (1998) An Sp1 binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in both men and women. J Bone Miner Res 13:1384–1389PubMedCrossRefGoogle Scholar
  15. 15.
    Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH (1998) Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women [see comments]. N Engl J Med 338:1016–1021PubMedCrossRefGoogle Scholar
  16. 16.
    Bernad M, Martinez ME, Escalona M, Gonzalez ML, Gonzalez C, Garces MV, Del Campo MT, Martin ME, Madero R, Carreno L (2002) Polymorphism in the type I collagen (COLIA1) gene and risk of fractures in postmenopausal women. Bone 30:223–228PubMedCrossRefGoogle Scholar
  17. 17.
    Ralston SH, Uitterlinden AG, Brandi ML, Balcells S, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Scollen S, Bustamante M, Husted LB, Carey AH, Diez-Perez A, Dunning AM, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Del Monte F, Pols HA, Reeve J, Reid DM, Renner W, Rivadeneira F, van Schoor NM, Sherlock RE, Ioannidis JP (2006) Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med 3(4):e90PubMedCrossRefGoogle Scholar
  18. 18.
    Garcia-Giralt N, Nogues X, Enjuanes A, Puig J, Mellibovsky L, Bay-Jensen A, Carreras R, Balcells S, Diez-Perez A, Grinberg D (2002) Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density. J Bone Miner Res 17:384–393PubMedCrossRefGoogle Scholar
  19. 19.
    Liu PY, Lu Y, Long JR, Xu FH, Shen H, Recker RR, Deng HW (2004) Common variants at the PCOL2 and Sp1 binding sites of the COL1A1 gene and their interactive effect influence bone mineral density in Caucasians. J Med Genet 41(10):752–757PubMedCrossRefGoogle Scholar
  20. 20.
    Yamada Y, Ando F, Niino N, Shimokata H (2005) Association of a –1997G-->;T polymorphism of the collagen Ialpha1 gene with bone mineral density in postmenopausal Japanese women. Hum Biol 77(1):27–36PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang YY, Lei SF, Mo XY, Wang YB, Li MX, Deng HW (2005) The –1997 G/T polymorphism in the COLIA1 upstream regulatory region is associated with hip bone mineral density (BMD) in Chinese nuclear families. Calcif Tissue Int 76(2):107–112PubMedCrossRefGoogle Scholar
  22. 22.
    Yazdanpanah N, Rivadeneira F, van Meurs JB, Zillikens MC, Arp P, Hofman A, Van Duijn CM, Pols HA, Uitterlinden AG (2007) The –1997 G/T and Sp1 polymorphisms in the collagen type I alpha1 (COLIA1) gene in relation to changes in femoral neck bone mineral density and the risk of fracture in the elderly: the Rotterdam Study. Calcif Tissue Int 81:18–25PubMedCrossRefGoogle Scholar
  23. 23.
    Stewart TL, Jin H, McGuigan FE, Albagha OM, Garcia-Giralt N, Bassiti A, Grinberg D, Balcells S, Reid DM, Ralston SH (2006) Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. J Clin Endocrinol Metab 91:3575–3583PubMedCrossRefGoogle Scholar
  24. 24.
    McCloskey EV, Spector TD, Eyres KS, Fern ED, O’Rourke N, Vasikaran S, Kanis JA (1993) The assessment of vertebral deformity: a method for use in population studies and clinical trials. Osteoporos Int 3:138–147PubMedCrossRefGoogle Scholar
  25. 25.
    Genant HK, Grampp S, Gluer CC, Faulkner KG, Jergas M, Engelke K, Hagiwara S, Van Kuijk C (1994) Universal standardization for dual X-ray absorptiometry: patient and phantom cross-calibration results [see comments]. J Bone Miner Res 9:1503–1514PubMedCrossRefGoogle Scholar
  26. 26.
    Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L (1993) Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 39:635–640PubMedGoogle Scholar
  27. 27.
    Brixen K, Nielsen HK, Eriksen EF, Charles P, Mosekilde L (1989) Efficacy of wheat germ lectin-precipitated alkaline phosphatase in serum as an estimator of bone mineralization rate: comparison to serum total alkaline phosphatase and serum bone Gla-protein [see comments]. Calcif Tissue Int 44:93–98PubMedCrossRefGoogle Scholar
  28. 28.
    Melkko J, Niemi S, Risteli L, Risteli J (1990) Radioimmunoassay of the carboxyterminal propeptide of human type I procollagen. Clin Chem 36:1328–1332PubMedGoogle Scholar
  29. 29.
    Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jones HW Jr, Rary JM (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci USA 74:1245–1249PubMedCrossRefGoogle Scholar
  30. 30.
    McGuigan FE, Ralston SH (2002) Single nucleotide polymorphism detection: allelic discrimination using TaqMan. Psychiatr Genet 12(3):133–136PubMedCrossRefGoogle Scholar
  31. 31.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265PubMedCrossRefGoogle Scholar
  32. 32.
    Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989PubMedCrossRefGoogle Scholar
  33. 33.
    Mann V, Ralston SH (2003) Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone 32:711–717PubMedCrossRefGoogle Scholar
  34. 34.
    Jin H, Stewart TL, van’t Hof RJ, Aspend RM, Ralston S (2007) A rare haplotype in the 5′ flank of the COLIA1 gene is enriched in hip fracture patients and reduces bone strength independent of BMD. Calcif Tissue Int 80:s25Google Scholar
  35. 35.
    Mann V, Hobson EE, Li B, Stewart TL, Grant SF, Robins SP, Aspden RM, Ralston SH (2001) A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 107:899–907PubMedCrossRefGoogle Scholar
  36. 36.
    Garcia-Giralt N, Enjuanes A, Bustamante M, Mellibovsky L, Nogues X, Carreras R, Diez-Perez A, Grinberg D, Balcells S (2005) In vitro functional assay of alleles and haplotypes of two COL1A1-promoter SNPs. Bone 36(5):902–908PubMedCrossRefGoogle Scholar
  37. 37.
    Bornstein P, McKay J, Morishima JK, Devarayalu S, Gelinas RE (1987) Regulatory elements in the first intron contribute to transcriptional control of the human alpha 1(I) collagen gene. Proc Natl Acad Sci USA 84:8869–8873PubMedCrossRefGoogle Scholar
  38. 38.
    Ptashne M (1986) Gene regulation by proteins acting nearby and at a distance. Nature 322:697–701PubMedCrossRefGoogle Scholar
  39. 39.
    Jin H, Albagha OME, van’t Hof RJ, Ralston S (2008) Promoter and intron 1 polymorphisms of COLIA1 predispose to osteoporosis by regulating transcription and altering binding of Sp1, NMP4 and osterix. Calcif Tissue Int 82(Suppl. 1):s44Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • L. B. Husted
    • 1
  • T. Harsløf
    • 1
  • N. Gonzalez-Bofill
    • 1
  • A. Schmitz
    • 2
  • M. Carstens
    • 1
  • L. Stenkjær
    • 1
  • B. L. Langdahl
    • 1
  1. 1.Department of Endocrinology and MetabolismAarhus University HospitalAarhus CDenmark
  2. 2.Department of Internal MedicineVejle SygehusVejleDenmark

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