Human Genetics

, Volume 114, Issue 3, pp 236–241 | Cite as

Analysis of heat-shock protein 70 gene polymorphisms and the risk of Parkinson’s disease

  • Yih-Ru Wu
  • Cheng-Kuang Wang
  • Chiung-Mei Chen
  • Yuying Hsu
  • Sih-Jing Lin
  • Yi-Ying Lin
  • Hon-Chung Fung
  • Kuo-Hsuan Chang
  • Guey-Jen Lee-Chen
Original Investigation

Abstract

Parkinson’s disease (PD) involves several genetic and environmental components. Heat-shock protein 70, a chaperone that is up-regulated in stress responses and that refolds protein, may be involved in the pathogenesis of PD. We have investigated the association of polymorphisms −110 A/C, +190 G/C, +1267 A/G, +2074 G/C, and +2437 G/C in the 5’ and coding regions of the HSP70-1, HSP70-2, and HSP70-hom genes with the risk of PD by screening DNA samples from 274 PD patients and 183 controls in assays based on the polymerase chain reaction. There was no statistically significant difference in genotype distribution between patients and controls for the three coding-region polymorphisms in HSP70-2 and HSP70-hom. However, for HSP70-1, the overall genotype distribution was significantly different at the −110 site (P=0.004) and tended to be different at the +190 site (P=0.012) between patients and controls. The frequencies of the −110 CC and +190 CC genotypes were significantly higher in PD patients than in controls (P=0.001 and 0.006, respectively). Both −110 CC (odds ratio: 2.91; 95% CI: 1.51–5.96; P=0.002) and +190 CC (odds ratio: 3.59; 95% CI: 1.53–9.88; P=0.006) genotypes were significantly associated with PD. Reporter constructs containing the −110 A allele cloned into a luciferase reporter plasmid drove marginally higher transcriptional activity of HSP70-1 compared with the −110 C allele in both control and heat-shocked IMR32 and 293 cells. Therefore, −110 A/C may be a functional polymorphism in the 5’ promoter region of HSP70-1 and may affect susceptibility to PD.

Notes

Acknowledgements

We thank the PD patients and normal controls for participating in this study. We also acknowledge Lai-Chu See for aid with the statistical analysis. Part of this work was supported by grant NSC90-2311-B-003-004 from the National Science Council, Executive Yuan, Republic of China.

References

  1. Abravaya K, Phillips B, Morimoto RI. (1991) Heat shock-induced interactions of heat shock transcription factors and the human hsp70 promoter examined by in vivo footprinting. Mol Cell Biol 11:586–592PubMedGoogle Scholar
  2. Aron Y, Busson M, Polla BS, Dusser D, Lockhart A, Swierczewski E, Favatier F (1999) Analysis of hsp70 gene polymorphism in allergic asthma. Allergy 54:165–170CrossRefPubMedGoogle Scholar
  3. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868CrossRefPubMedGoogle Scholar
  4. Bonifati V, Rizzu P, Baren MJ van, Schaap O, Breedveld GJ, Krieger E, Dekker MCJ, Squitieri F, Ibanez P, Joosse M, Dongen JW van, Vanacore N, Swieten JC van, Brice A, Meco G, Duijn CM van, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256-259CrossRefPubMedGoogle Scholar
  5. Calne DB, Snow BJ, Lee C (1992) Criteria for diagnosing Parkinson’s disease. Ann Neurol 32:S125–S127PubMedGoogle Scholar
  6. Cascino I, Sorrentino R, Tosi R (1993) Strong genetic association between HLA-DR3 and a polymorphic variation in the regulatory region of the HSP70-1 gene. Immunogenetics 37:177–182PubMedGoogle Scholar
  7. Chai Y, Koppenhafer SL, Bonini NM, Paulson HL (1999) Analysis of the role of heat shock protein (HSP) molecular chaperones in polyglutamine disease. J Neurosci 19:10338–10347PubMedGoogle Scholar
  8. Chan HY, Warrick JM, Gray-Board, Paulson HL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9:2811–2820CrossRefPubMedGoogle Scholar
  9. Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, Dillmann WH, Zoghbi HY (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10:1511–1518CrossRefPubMedGoogle Scholar
  10. Deguchi Y, Kishimoto S (1990) Enhanced expression of the heat shock protein gene in peripheral blood mononuclear cells of patients with active systemic lupus erythematosus. Ann Rheum Dis 49:893–895PubMedGoogle Scholar
  11. Dhillon VB, McCallum S, Norton P, Twomey BM, Erkeller-Yuksel F, Lydyard P, Isenberg DA, Latchman DS (1993) Differential heat shock protein overexpression and its clinical relevance in systemic lupus erythematosus. Ann Rheum Dis 52:436–442PubMedGoogle Scholar
  12. Easki M, Furuse M, Matsumoto T, Aoyagi K, Jo Y, Yamagata H, Nakano H (1999) Polymorphism of heat-shock protein gene HSP70-2 in Crohn disease: possible genetic marker for two forms of Crohn disease. Sacand J Gastroenterol 34:703–707CrossRefGoogle Scholar
  13. Favatier F, Jacquier-Sarlin MR, Swierczewski E, Polla BS (1999) Polymorphism in the regulatory sequence of the human hsp70–1 gene does not affect heat shock factor binding or heat shock protein synthesis. Cell Mol Life Sci 56:701–708CrossRefPubMedGoogle Scholar
  14. Fraile A, Nieto A, Mataran L, Martin J (1998) HSP70 gene polymorphisms in ankylosing spondylitis. Tissue Antigens 51:382–385PubMedGoogle Scholar
  15. Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355:33-45PubMedGoogle Scholar
  16. Gwinn-Hardy K (2002) Genetics of Parkinsonism. Mov Disord 17:645–656CrossRefPubMedGoogle Scholar
  17. Hill WG (1974) Estimation of linkage disequilibrium in randomly mating populations. Heredity 33:229–239PubMedGoogle Scholar
  18. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of parkin. Cell 105:891–902CrossRefPubMedGoogle Scholar
  19. Ishihara M, Ohno S, Ishida T, Mizuki N, Ando H, Naruse T, Ishihara H, Inoko H (1995) Genetic polymorphisms of the TNFB and HSP70 genes located in the human major histocompatibility complex in sarcoidosis. Tissue Antigens 46:59–62PubMedGoogle Scholar
  20. Kaarniranta K, Oksala N, Karjalainen HM, Suuronen T, Sistonen L, Helminen HJ, Salminen A, Lammi MJ (2002) Neuronal cells show regulatory differences in the hsp70 gene response. Mol Brain Res 101:136–140CrossRefPubMedGoogle Scholar
  21. Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–1840CrossRefPubMedGoogle Scholar
  22. Lang AE, Lozano AM (1998) Parkinson’s disease (first of two parts). N Engl J Med 339:1044–1053PubMedGoogle Scholar
  23. Milner CM, Campbell RD (1990) Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32:242–251PubMedGoogle Scholar
  24. Milner CM, Campbell RD (1992) Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics 36:357–362PubMedGoogle Scholar
  25. Niino M, Kikuchi S, Fukazawa T, Yabe I, Sasaki H, Tashiro K (2000) Heat shock protein 70 gene polymorphism in Japanese patients with multiple sclerosis. Tissue Antigens 58:93–96CrossRefGoogle Scholar
  26. Parsell DA, Lindquist S (1993) The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet 27:437–496PubMedGoogle Scholar
  27. Partanen J, Milner C, Campbell RD, Maki M, Lipsanen V, Koskimies S (1993) HLA-linked heat-shock protein 70 (HSP70-2) gene polymorphism and celiac disease. Tissue Antigens 41:15–19PubMedGoogle Scholar
  28. Pociot F, Rønningen KS, Nerup J (1993) Polymorphic analysis of the human MHC-linked heat shock 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). Scand J Immunol 38:491–495PubMedGoogle Scholar
  29. Pugliese A, Awdeh ZL, Galluzzo A, Yunis EJ, Alper CA, Eisenbarth GS (1992) No independent association between HSP70 gene polymorphism and IDDM. Diabetes 41:788–791PubMedGoogle Scholar
  30. Ramos-Arroyo MA, Feijoo E, Sanchez-Valverde F, Aranburu E, Irisarri N, Olivera JE, Valiente A (2001) Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain). Hum Immunol 62:821–825CrossRefPubMedGoogle Scholar
  31. Shimizu S, Nomura K, Ujihara M, Sakamoto K, Shibata H, Susuki T, Demura H (1996) An allele-specific abnormal transcript of the heat shock protein 70 gene in patients with major depression. Biochem Biophys Res Commun 219:745–752CrossRefPubMedGoogle Scholar
  32. Silva HR de, Khan NL, Wood NW (2000) The genetics of Parkinson’s disease. Curr Opin Genet Dev 10:292–298CrossRefPubMedGoogle Scholar
  33. Vargas-Alarcon G, Londono JD, Hernandez-Pacheco G, Gamboa R, Castillo E, Pacheco-Tena C, Cardiel MH, Granados J, Burgos-Vargas R (2002) Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies. Ann Rheum Dis 61:48–51CrossRefPubMedGoogle Scholar
  34. Vignola AM, Chanez P, Polla BS, Vic P, Godard P, Bousquet J (1995) Increased expression of heat shock protein 70 on airway cells in asthma and chronic bronchitis. Am J Respir Cell Mol Biol 13:683–691PubMedGoogle Scholar
  35. Vinasco J, Beraun Y, Nieto A, Fraile A, Pareja E, Mataran L, Martin J (1997) Heat shock protein 70 gene polymorphisms in rheumatoid arthritis. Tissue Antigens 50:71–73PubMedGoogle Scholar
  36. Young RA, Elliott TJ (1989) Stress proteins, infection and immune surveillance. Cell 59:5–8PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yih-Ru Wu
    • 1
  • Cheng-Kuang Wang
    • 2
    • 3
  • Chiung-Mei Chen
    • 1
  • Yuying Hsu
    • 2
  • Sih-Jing Lin
    • 2
  • Yi-Ying Lin
    • 4
  • Hon-Chung Fung
    • 1
  • Kuo-Hsuan Chang
    • 1
  • Guey-Jen Lee-Chen
    • 2
  1. 1.Second Department of Neurology, Chang Gung Memorial Hospital and College of MedicineChang Gung UniversityTaipeiTaiwan
  2. 2.Department of Life ScienceNational Taiwan Normal UniversityTaipeiTaiwan
  3. 3.Jen-Teh Junior College of Medicine, Nursing and ManagementMiaoliTaiwan
  4. 4.School of Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan

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