Advertisement

Molecular Biology Reports

, Volume 39, Issue 6, pp 6661–6669 | Cite as

Association between α1-antichymotrypsin signal peptide −15A/T polymorphism and the risk of Alzheimer’s disease: a meta-analysis

  • Fulin Guan
  • Jiaao Gu
  • Fulan Hu
  • Yulan Zhu
  • Weizhi WangEmail author
Article

Abstract

No consensus has been recently reached at the relationship between the α1-antichymotrypsin (ACT) signal peptide −15A/T polymorphism and Alzheimer’s disease (AD) risk. Thus, our study aimed to better assess this association by performing a meta-analysis, including 4,212 cases and 4,039 controls from 29 studies. Odds ratios (ORs) with the 95% confidence interval (CI) were used to assess the strength of relationship between ACT −15A/T polymorphism and AD risk. Overall, a borderline statistically significant association was detected under recessive model comparison in all subjects (AA vs. AT+TT: OR 1.12, 95% CI 1.01–1.25, P = 0.04). But in subgroup analysis by ethnicity, no significant association was found in Caucasians, Asians, or Africans. Moreover, after exclusion of one study which affect the heterogeneity, the ACT A allele and AA genotype were statistically associated with late-onset AD (LOAD) risk (AA vs. TT: OR 1.25, 95% CI 1.06–1.48, P = 0.007, A vs. T: OR 1.12, 95% CI 1.03–1.21, P = 0.008), especially in Caucasians. In conclusion, our study suggests that the common α1-antichymotrypsin signal peptide −15A/T polymorphism may not be a major risk factor for AD. However, the polymorphism is capable of increasing LOAD risk.

Keywords

α1-Antichymotrypsin Alzheimer’s disease Meta-analysis Polymorphism 

Notes

Acknowledgment

This study was supported by National Natural Science Foundation of China (No. 30470583).

Conflict of Interest

None declared.

References

  1. 1.
    Katzman RN (1996) Medical progress: Alzheimer’s disease. N Engl J Med 274:964–973Google Scholar
  2. 2.
    Styren SD, Kamboh MI, DeKosky ST (1998) Expression of differential immune factors in temporal cortex and cerebellum: the role of alpha-1-antichymotrypsin, apolipoprotein E, and reactive glia in the progression of Alzheimer’s disease. J Comp Neurol 396:511–520PubMedCrossRefGoogle Scholar
  3. 3.
    Abraham CR, Selkoe DJ, Potter H (1988) Immunochemical identification of the serine protease inhibitor α1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell 52:487–501PubMedCrossRefGoogle Scholar
  4. 4.
    Ma J, Yee A, Brewer HB, Das S, Potter H (1994) Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 372:92–94PubMedCrossRefGoogle Scholar
  5. 5.
    Nilsson LN, Bales KR, DiCarlo G, Gordon MN, Morgan D, Paul SM, Potter H (2001) α1-Antichymotrypsin promotes β-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J Neurosci 21:1444–1451PubMedGoogle Scholar
  6. 6.
    Nilsson LN, Arendash GW, Leighty RE, Costa DA, Low MA, Garcia MF, Cracciolo JR, Rojiani A, Wu X, Bales KR, Paul SM, Potter H (2004) Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation. Neurobiol Aging 25:1153–1167PubMedCrossRefGoogle Scholar
  7. 7.
    Padmanabhan J, Levy M, Dickson DW, Potter H (2006) Alpha1-antichymotrypsin, an inflammatory protein over expressed in Alzheimer’s disease brain, induces tau phosphorylation in neurons. Brain 129:3020–3034PubMedCrossRefGoogle Scholar
  8. 8.
    Harigaya Y, Shoji M, Nakamura T, Matsubara E, Hosoda K, Hirai S (1995) α1-Antichymotrypsin level in cerebrospinal fluid is closely associated with late onset Alzheimer’s disease. Intern Med 34:481–484PubMedCrossRefGoogle Scholar
  9. 9.
    Lieberman J, Schleissner L, Tachiki KH, Kling AS (1995) Serum α1-antichymotrypsin level as a marker for Alzheimer-type dementia. Neurobiol Aging 16:747–753PubMedCrossRefGoogle Scholar
  10. 10.
    Kalsheker NA (1996) Alpha 1-antichymotrypsin. Int J Biochem Cell B 28:961–964CrossRefGoogle Scholar
  11. 11.
    Faber JP, Polle W, Olek K, Baumann U, Carlson J, Lindmark B, Eriksson S (1993) The molecular basis of α1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. J Hepatol 18:313–321PubMedCrossRefGoogle Scholar
  12. 12.
    Kamboh MI, Sanghera DK, Ferrell RE, DeKosky ST (1995) APOE4-associated Alzheimer’s disease risk is modified by α1-antichymotrypsin polymorphism. Nat Genet 10:486–488PubMedCrossRefGoogle Scholar
  13. 13.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315:629–634CrossRefGoogle Scholar
  14. 14.
    Blennow K, De Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403PubMedCrossRefGoogle Scholar
  15. 15.
    Muramatsu T, Matsushita S, Arai H, Sasaki H, Higuchi S (1996) α1-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease. J Neural Transm 103:1205–1210PubMedCrossRefGoogle Scholar
  16. 16.
    Thome J, Baumer A, Kornhuber J, Rosler R, Riederer P (1995) Alpha-1-antichymotrypsin bi-allele polymorphism, apolipoprotein-E tri-allele polymorphism and genetic risk for Alzheimer’s syndrome. J Neural Transm 102:207–212Google Scholar
  17. 17.
    Nacmias B, Tedde A, Latorraca S, Piacentini S, Braco L, Amaducci L, Guarniere BM, Petrucci C, Ortenzi L, Sorbi S (1996) Apolipoprotein E and α1-antichymotrypsin gene polymorphism in Alzheimer’s disease. Ann Neurol 40:678–680PubMedCrossRefGoogle Scholar
  18. 18.
    Ezquerra M, Blesa R, Tolosa E, Ballesta F, Oliva R (1998) α-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease in the Spanish population. Neurosci Lett 240:107–109PubMedCrossRefGoogle Scholar
  19. 19.
    George-Hyslop St PH (2000) Molecular genetics of Alzheimer’s disease. Biol Psychiatry 47:183–199CrossRefGoogle Scholar
  20. 20.
    Ki CS, Na DL, Kim HJ, Kim JW (2001) Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer’s disease. Neurosci Lett 302:69–72PubMedCrossRefGoogle Scholar
  21. 21.
    Schwab SG, Bagli M, Papassotiropoulos A, Jessen F, Maier W, Rao ML, Heun R (1999) Alpha-1-antichymotrypsin gene polymorphism and risk for sporadic Alzheimer’s disease in a German population. Dement Geriatr Cogn 10(6):469–472CrossRefGoogle Scholar
  22. 22.
    Wang XY, DeKosky ST, Luedecking-Zimmer E, Ganguli M, Kamboh MI (2002) Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease. Hum Genet 110:356–365PubMedCrossRefGoogle Scholar
  23. 23.
    Perry RT, Collins JS, Harrell LE, Acton RT, Go RC (2001) Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls. Am J Med Genet B 105:332–342CrossRefGoogle Scholar
  24. 24.
    Sodeyama N, Yamada M, Itoh Y, Suematsu N, Matsushita M, Otomo E, Mizusawa H (1999) Lack of genetic associations of alpha-1-antichymotrypsin polymorphism with Alzheimer-type neuropathological changes or sporadic Alzheimer’s disease. Dement Geriatr Cogn 10:221–225CrossRefGoogle Scholar
  25. 25.
    Morgan K, Morgan L, Carpenter K, Lowe J, Lam L, Cave S, Xuereb J, Wischik C, Harrington C, Kalsheker NA (1997) Microsatellite polymorphism of the α1-antichymotrypsin gene locus associated with sporadic Alzheimer’s disease. Hum Genet 99:27–31PubMedCrossRefGoogle Scholar
  26. 26.
    Wang YC, Liu TY, Liu HC, Chi CW, Sim CB, Tsai SJ, Hong CJ (1999) No association between alpha-1-antichymotrypsin polymorphism and Alzheimer’s disease in Chinese. Neuropsychobiology 40(2):67–70PubMedCrossRefGoogle Scholar
  27. 27.
    Kim KW, Jhoo JH, Lee KU, Lee DY, Lee JH, Youn JY, Lee BJ, Han SH, Woo JI (2000) No association between alpha-1-antichymotrypsin polymorphism and Alzheimer’s disease in Koreans. Am J Med Genet 91:355–358PubMedCrossRefGoogle Scholar
  28. 28.
    Helisalmi S, Mannermaa A, Lehtovirta M, Ryynanen M, Riekkinen P Sr, Soininen H (1997) No association between α1-antichymotrypsin polymorphism, apolipoprotein E and patients with late-onset Alzheimer’s disease. Neurosci Lett 231:56–58PubMedCrossRefGoogle Scholar
  29. 29.
    Didierjean O, Martinez M, Campion D, Hannequin D, Dubois B, Martin C, Puel M, Thomas Anterion C, Pasquier F, Moreau O, Babron MC, Penet C, Agid Y, Clerget-Darpoux F, Frebourg T, Brice A (1997) No effect of the α1-antichymotrypsin A allele in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 63:103–105PubMedCrossRefGoogle Scholar
  30. 30.
    Talbot C, Houlden H, Craddock N, Crook R, Hutton M, Lendon C, Prihar G, Morris JC, Hardy J, Goate A (1996) Polymorphism in AACT gene may lower age of onset of Alzheimer’s disease. Neuroreport 7:534–536PubMedCrossRefGoogle Scholar
  31. 31.
    Martin TR, Calella AM, Silva S, Munna E, Modena P, Chiesa R, Terrevazzi S, Ruggieri RM, Palermo R, Piccoli F, Confalonieri R, Tiraboschi P, Fragiacomo C, Quadri P, Lucca U, Forloni G (2000) Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn 11:239–244CrossRefGoogle Scholar
  32. 32.
    Haines JL, Pritchard ML, Saunders AM, Schildkraut JM, Growdon JH, Gaskell PC, Farrer LA, Auerbach SA, Gusella JF, Locke PA, Rosi BL, Yamaoka L, Small GW, Conneally PM, Roses AD, Pericak-vance MA (1996) No genetic effect of α1-antichymotrypsin in Alzheimer disease. Genomics 33:53–56PubMedCrossRefGoogle Scholar
  33. 33.
    Scacchi R, Gambina G, Ruggeri M, Martini MC, Ferrari G, Silvestri M, Schiavon R, Corbo RM (1999) Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer’s disease. Neurosci Lett 259:33–36PubMedCrossRefGoogle Scholar
  34. 34.
    Mcilroy SP, Vahidassr MD, Savage DA, Lloyd F, Patterson CC, Lawson JT, Passmore AP (2000) Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer’s disease in Northern Ireland. Int J Geriatr Psych 15:260–266CrossRefGoogle Scholar
  35. 35.
    Tang GM, Jiang SD, Zhang MY, Lin SC, Qian YP, Wu XD, Wang DX, Jin TG, Gu NF (2000) Genetic association study between α1-antichymotrypsin polymorphism and Alzheimer disease in Chinese Han population. Am J Med Genet B 96:133–135CrossRefGoogle Scholar
  36. 36.
    Yamanaka H, Kamimura K, Tanahashi H, Takahashi K, Asada T, Tabira T (1998) Genetic risk factors in Japanese Alzheimer’s disease patients: α1-ACT, VLDLR, and ApoE. Neurobiol Aging 19:S43–S46PubMedCrossRefGoogle Scholar
  37. 37.
    Lamb H, Christie J, Singleton AB, Leake A, Perry RH, Ince PG, McKeith IG, Melton LM, Edwardson JA, Morris CM (1998) Apolipoprotein E and alpha-1 antichymotrypsin polymorphism genotyping in Alzheimer’s disease and in dementia with Lewy bodies. Neurology 50:388–391PubMedGoogle Scholar
  38. 38.
    Yoshiiwa A, Kamino K, Yamamoto H, Kobayashi T, Imagawa M, Nonomura Y, Yoneda H, Sakai T, Nishiwaki Y, Sato N, Rakugi H, Miki T, Ogihara T (1997) α1-Antichymotrypsin as a risk modifier for late-onset Alzheimer’s disease in Japanese apolipoprotein E ε 4 allele carriers. Ann Neurol 42:115–117PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshizawa T, Yamakawa-Kobayashi K, Hamaguchi H, Shoji S (1997) α1-Antichymotrypsin polymorphism in Japanese cases of Alzheimer’s disease. J Neurol Sci 152:136–139PubMedCrossRefGoogle Scholar
  40. 40.
    Durany N, Ravid R, Riederer P, Cruz-Sanchez FF (2000) Increased frequency of the T allele in cerebral amyloid angiopathy. Neuropathology 20:184–189PubMedCrossRefGoogle Scholar
  41. 41.
    Retz W, Thome J, Durany N, Harsanyi A, Retz-Junginger P, Kornhuber J, Riederer P, Rosler M (2001) Potential genetic markers of sporadic Alzheimer’s dementia. Psychiat Genet 11:115–122CrossRefGoogle Scholar
  42. 42.
    Egensperger R, Kösel S, Schnopp NM, Mehraein P, Graeber MB (1997) Association of the mitochondrial tRNA A4336G mutation with Alzheimer’s and Parkinson’s diseases. Neuropath Appl Neuro 23:315–321CrossRefGoogle Scholar
  43. 43.
    Itabashi S, Arai H, Matsui T, Matsushita S, Muramatsu T, Higuchi S, Trojanowski JQ, Sasaki H (1998) Absence of association of α1-antichymotrypsin polymorphisms with Alzheimer’s disease: a report on autopsy-confirmed cases. Exp Neurol 151:237–240PubMedCrossRefGoogle Scholar
  44. 44.
    Hernández-Charro B, Moreno S, Valiente A, Manubens JM, Villar MD, Ramos-Arroyo MA (2004) ACT/AA polymorphism could duplicate the APOE*ε 4-associated Alzheimer’s disease risk. Med Clin (Barc) 123(7):251–254CrossRefGoogle Scholar
  45. 45.
    Murphy GM, Sullivan EV, Gallagher-Thompson D, Thompson LW, Van Duijn CM, Forno LS, Ellis WG, Jagust WJ, Yesavage J, Tinklenberg JR (1997) No association between the alpha 1-antichymotrypsin A allele and Alzheimer’s disease. Neurology 48(5):1313–1316PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Fulin Guan
    • 1
  • Jiaao Gu
    • 3
  • Fulan Hu
    • 2
  • Yulan Zhu
    • 1
  • Weizhi Wang
    • 1
    Email author
  1. 1.Department of NeurologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of EpidemiologyPublic Health College of Harbin Medical UniversityHarbinChina
  3. 3.Department of OrthopedicsThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina

Personalised recommendations