Digestive Diseases and Sciences

, Volume 54, Issue 2, pp 369–376 | Cite as

Study of the Association Between Polymorphisms of the COL1A1 Gene and HBV-Related Liver Cirrhosis in Chinese Patients

  • Yun-Peng Zhao
  • Hao Wang
  • Meng Fang
  • Qiang Ji
  • Zai-Xing Yang
  • Chun-Fang Gao
Original Article


To investigate the association between polymorphisms of the COL1A1 gene and liver cirrhosis. A total of 111 liver cirrhotic patients and 95 matched controls were recruited. Polymorphisms −1997T>G, −1663 ins/del T and −1363C>G of the COL1A1 gene were detected by direct sequencing. The activities of the putative promoters containing these polymorphisms were analyzed by means of the reporter gene system. No polymorphism at −1663 ins/del T was observed in any subject. Linkage disequilibrium was shown between −1997T>G and −1363C>G. The frequency of haplotype −1997T/−1363C was significantly higher in patients than that in controls. The putative promoters containing −1997T/−1363C resulted in higher reporter gene activity in LX-2. Strong transcriptional inhibition by IFNγ was shown in both cells. The T allele at −1997 of COL1A1 is crucial to the increased transcriptional activity. COL1A1 gene polymorphism might be associated with liver fibrogenesis.


Cirrhosis Fibrosis Collagen Polymorphism Promoter 



This work was supported by the National Natural Science Foundation of China (No. 30270605 and No. 30571774). The authors are grateful for the kindly supply of LX-2 cell line by Professor Dr Scott L. Friedman from the USA.

Supplementary material

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  1. 1.
    Gressner AM, Schuppan D (1999) Cellular and molecular pathobiology, pharmacological intervention, and biochemical assessment of liver fibrosis. In: Bircher J, Benhamou J-P, McIntyre N, Rizzetto M, Rodes J (eds) Clinical hepatology, vol 1, 2nd edn. Oxford Medical Publications, Oxford, pp 607–627Google Scholar
  2. 2.
    Chu CM, Liaw YF, Hepatitis B (2006) Virus-related cirrhosis: natural history and treatment. Semin Liver Dis 26:142–52. doi: 10.1055/s-2006-939752 PubMedCrossRefGoogle Scholar
  3. 3.
    Okazaki I, Yonezawa Y, Watanabe T, Mayne R, Ninomiya T (2003) New insights into the extracellular matrix. In: Okazaki I, Ninomiya Y, Friedman SL, Tanikawa K (eds) Extracellular matrix and the liver. Academic Press, Elsevier Science, pp 3–22Google Scholar
  4. 4.
    Karsenty G, Park RW (1995) Regulation of type I collagen gene expression. Int Rev Immunol 12:177–185. doi: 10.3109/08830189509056711 PubMedCrossRefGoogle Scholar
  5. 5.
    Tanaka K, Matsumoto Y, Nakatani F, Iwamoto Y, Yamada Y (2000) A zinc finger transcription factor, alphaA-crystallin binding protein 1, is a negative regulator of the chondrocyte-specific enhancer of the alpha1(II) collagen gene. Mol Cell Biol 20:4428–4435. doi: 10.1128/MCB.20.12.4428-4435.2000 PubMedCrossRefGoogle Scholar
  6. 6.
    Hasegawa T, Takeuchi A, Miyaishi O, Xiao H, Mao J, Isobe K (2000) PTRF (polymerase I and transcript-release factor) is tissue-specific and interacts with the BFCOL1 (binding factor of a type-I collagen promoter) zinc-finger transcription factor which binds to the two mouse type-I collagen gene promoters. Biochem J 347(Pt 1):55–59. doi: 10.1042/0264-6021:3470055 PubMedCrossRefGoogle Scholar
  7. 7.
    Chen A, Davis BH (2000) The DNA binding protein BTEB mediates acetaldehyde-induced, jun N-terminal kinase-dependent alphaI(I) collagen gene expression in rat hepatic stellate cells. Mol Cell Biol 20:2818–2826. doi: 10.1128/MCB.20.8.2818-2826.2000 PubMedCrossRefGoogle Scholar
  8. 8.
    Xu Y, Wang L, Buttice G, Sengupta PK, Smith BD (2004) Major histocompatibility class II transactivator (CIITA)mediates repression of collagen (COL1A2) transcription by interferon gamma (IFN-gamma). J Biol Chem 279:41319–41332. doi: 10.1074/jbc.M404174200 PubMedCrossRefGoogle Scholar
  9. 9.
    Ghosh AK, Bhattacharyya S, Mori Y, Varga J (2006) Inhibition of collagen gene expression by interferon-gamma: novel role of the CCAAT/enhancer binding protein beta(C/EBPbeta). J Cell Physiol 207:251–260. doi: 10.1002/jcp.20559 PubMedCrossRefGoogle Scholar
  10. 10.
    Gao CF, Wang H, Wu YA, Kong XT (1999) Effect of cytokines on promoter activity in mouse α(I)procollagen gene. J Med Coll PLA 14:12–16Google Scholar
  11. 11.
    Gao CF, Wang H, Wang AH, Wan WD, Wu YA, Kong XT (2004) Transcriptional regulation of human α1(I) procollagen gene in dermal fibroblasts. World J Gastroenterol 10:1447–1451PubMedGoogle Scholar
  12. 12.
    Marini JC, Forlino A, Cabral WA et al (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209–221. doi: 10.1002/humu.20429 PubMedCrossRefGoogle Scholar
  13. 13.
    Pollitt R, McMahon R, Nunn J et al (2006) Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV. Hum Mutat 27:716. doi: 10.1002/humu.9430 PubMedCrossRefGoogle Scholar
  14. 14.
    Mann V, Ralston SH (2003) Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone 32:711–717. doi: 10.1016/S8756-3282(03)00087-5 PubMedCrossRefGoogle Scholar
  15. 15.
    Inagaki Y, Nemoto T, Kushida M et al (2003) Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice. Hepatology 38:890–899PubMedGoogle Scholar
  16. 16.
    Buttner C, Skupin A, Rieber EP (2004) Transcriptional activation of the type I collagen genes COL1A1 and COL1A2 in fibroblasts by interleukin-4: analysis of the functional collagen promoter sequences. J Cell Physiol 198:248–258. doi: 10.1002/jcp.10395 PubMedCrossRefGoogle Scholar
  17. 17.
    Infante-Rivard C, Esnaola S, Villencuve JP (1987) Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhosis. Hepatology 7:660–664. doi: 10.1002/hep.1840070408 PubMedCrossRefGoogle Scholar
  18. 18.
    Xu L, Hui AY, Albanis E et al (2005) Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut 54:142–151. doi: 10.1136/gut.2004.042127 PubMedCrossRefGoogle Scholar
  19. 19.
    Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121. doi: 10.1002/gepi.10252 PubMedCrossRefGoogle Scholar
  20. 20.
    Bataller R, North KE, Brenner DA (2003) Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 37:493–503. doi: 10.1053/jhep.2003.50127 PubMedCrossRefGoogle Scholar
  21. 21.
    Wang H, Mengsteab S, Tag CG et al (2005) Transforming growth factor-β1 gene polymorphisms are associated with severity of liver fibrosis in Caucasians with chronic hepatitis C infection. World J Gastroenterol 11:1929–1936PubMedGoogle Scholar
  22. 22.
    Yata Y, Scanga A, Gillan A et al (2003) Dnase I-hypersensitive sites enhance alpha1(1) collagen gene expression in hepatic stellate cells. Hepatology 37:267–276. doi: 10.1053/jhep.2003.50067 PubMedCrossRefGoogle Scholar
  23. 23.
    Papakrivopoulou J, Lindahl GE, Bishop JE, Laurent GJ (2004) Differential roles of extracellular signal-regulated kinase 1/2 and p38(MAPK) in mechanical load-induced procollagen alpha(1)(I) gene expression in cardiac fibroblasts. Cardiovasc Res 61:736–744. doi: 10.1016/j.cardiores.2003.12.018 PubMedCrossRefGoogle Scholar
  24. 24.
    Tsukada S, Westwick JK, Ikejima K, Sato N, Rippe RA (2005) SMAD and p38 MAPK signaling pathways independently regulate alpha1(1)collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells. J Biol Chem 280:10055–10064. doi: 10.1074/jbc.M409381200 PubMedCrossRefGoogle Scholar
  25. 25.
    Kubota K, Okazaki J, Louie O, Kent KC, Liu B (2003) TGF-beta stimulates collagen (I) in vascular smooth muscle cells via a short element in the proximal collagen promoter. J Surg Res 109:43–50. doi: 10.1016/S0022-4804(02)00037-9 PubMedCrossRefGoogle Scholar
  26. 26.
    Jimenez SA, Varga J, Olsen A et al (1994) Functional analysis of human alpha 1(I) procollagen gene promoter. Differential activity in collagen-producing and non-producing cells and response to transforming growth factor beta 1. J Biol Chem 269:12684–12691PubMedGoogle Scholar
  27. 27.
    Kern B, Shen J, Starbuck M, Karsenty G (2001) Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes. J Biol Chem 276:7101–7107. doi: 10.1074/jbc.M006215200 PubMedCrossRefGoogle Scholar
  28. 28.
    Inagaki Y, Kushida M, Higashi K et al (2005) Cell type-specific intervention of transforming growth factor beta/smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology 129:259–268. doi: 10.1053/j.gastro.2005.03.088 PubMedCrossRefGoogle Scholar
  29. 29.
    Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I (2003) Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction with YB-1 with Smad3. J Biol Chem 278:43470–43479. doi: 10.1074/jbc.M302339200 PubMedCrossRefGoogle Scholar
  30. 30.
    Lee KS, Song HR, Cho TJ et al (2006) Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. Hum Mutat 27:599. doi: 10.1002/humu.9423 PubMedCrossRefGoogle Scholar
  31. 31.
    Stewart TL, Jin H, McGuigan FE et al (2006) Haplotypes defined by promoter and intron 1 polymorphisms of the COL1A1 gene regulate bone mineral density in women. J Clin Endocrionol Metab 91:3575–3583. doi: 10.1210/jc.2005-2651 CrossRefGoogle Scholar
  32. 32.
    Garcia-Giralt N, Enjuanes A, Bustamante M et al (2005) In vitro functional assay of alleles and haplotypes of two COL1A1-promoter SNPs. Bone 36:902–908. doi: 10.1016/j.bone.2004.12.012 PubMedCrossRefGoogle Scholar
  33. 33.
    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 77:27–36. doi: 10.1353/hub.2005.0035 PubMedCrossRefGoogle Scholar
  34. 34.
    Riquet FB, Tan L, Choy BK et al (2001) YY1 is a positive regulator of transcription of the Col1a1 gene. J Biol Chem 276:38665–38672. doi: 10.1074/jbc.M009881200 PubMedCrossRefGoogle Scholar
  35. 35.
    Armelin-Correa LM, Lin CJ, Barbosa A et al (2005) Characterization of human collagen XVIII promoter 2: interaction of Sp1, Sp3 and YY1 with the regulatory region and a SNP that increases transcription in hepatocytes. Matrix Biol 24:550–559. doi: 10.1016/j.matbio.2005.08.003 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Yun-Peng Zhao
    • 1
  • Hao Wang
    • 2
  • Meng Fang
    • 1
  • Qiang Ji
    • 1
  • Zai-Xing Yang
    • 2
  • Chun-Fang Gao
    • 1
  1. 1.Department of Laboratory Medicine, Eastern Hepatobiliary HospitalSecond Military Medical UniversityShanghaiChina
  2. 2.Department of Laboratory Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina

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