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Association between HFE polymorphisms and susceptibility to Alzheimer’s disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls

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Abstract

Whether the variations in the hemochromatosis (HFE) gene increase Alzheimer’s disease (AD) risk is still undetermined. We performed a meta-analysis in order to systematically summarize the possible association. Studies were identified by searching PUBMED, Web of Science and EMBASE databases complemented with screening the references of the retrieved studies. The association was measured using random-effect or fixed-effect odds ratio (OR) combined with 95% confidence intervals (CIs) according to the studies’ heterogeneity. For C282Y polymorphism, we did not find any association using data from 22 studies including 4,365 cases and 8,652 controls. For H63D polymorphism, on the basis of 2,795 cases and 7,424 controls from 17 studies, we observed a significant association (allele contrast: OR = 0.902, 95% CI = 0.819–0.994, P = 0.037; minor-allele-dominant model: OR = 0.887, 95% CI = 0.790–0.996, P = 0.043). No publication bias was detected in this meta-analysis. The synthesis of available evidence supports mutant of HFE H63D polymorphism plays a protective role for AD risk.

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References

  1. Smith M, Harris P, Sayre L, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866

    Article  PubMed  CAS  Google Scholar 

  2. Smith MA, Perry G (1995) Free radical damage, iron, and Alzheimer’s disease. J Neurol Sci 134(Suppl):92–94

    Google Scholar 

  3. Kala S, Hasinoff B, Richardson J (1996) Brain samples from Alzheimer’s patients have elevated levels of loosely bound iron. Int J Neurosci 86:263–269

    Article  PubMed  CAS  Google Scholar 

  4. Bothwell TH, MacPhail AP (1998) Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol 35:55–71

    PubMed  CAS  Google Scholar 

  5. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    PubMed  CAS  Google Scholar 

  6. DerSimonian R, Kacker R (2007) Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 28:105–114. doi:10.1016/j.cct.2006.04.004

    Article  PubMed  Google Scholar 

  7. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  PubMed  CAS  Google Scholar 

  8. Kauwe J, Bertelsen S, Mayo K, Cruchaga C, Abraham R, Hollingworth P, Harold D, Owen M, Williams J, Lovestone S (2010) Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimers disease. Am J Med Genet B Neuropsychiatr Genet 153B(4):955–959

    Google Scholar 

  9. Nandar W, Connor JR (2011) HFE gene variants affect iron in the brain. J Nutr 141:729S–739S. doi:10.3945/jn.110.130351

    Article  PubMed  CAS  Google Scholar 

  10. Ajioka RS, Levy JE, Andrews NC, Kushner JP (2002) Regulation of iron absorption in HFE mutant mice. Blood 100:1465–1469. doi:10.1182/blood-2001-11-0037

    Article  PubMed  CAS  Google Scholar 

  11. Parkkila S, Niemela O, Britton RS, Fleming RE, Waheed A, Bacon BR, Sly WS (2001) Molecular aspects of iron absorption and HFE expression. Gastroenterology 121:1489–1496

    Article  PubMed  CAS  Google Scholar 

  12. Chua AC, Drake SF, Herbison CE, Olynyk JK, Leedman PJ, Trinder D (2006) Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse. J Hepatol 44:176–182. doi:10.1016/j.jhep.2005.08.012

    Article  PubMed  CAS  Google Scholar 

  13. Fleming RE, Britton RS (2006) Iron Imports VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 290:G590–G594. doi:10.1152/ajpgi.00486.2005

    Article  PubMed  CAS  Google Scholar 

  14. Moalem S, Percy ME, Andrews DF, Kruck TP, Wong S, Dalton AJ, Mehta P, Fedor B, Warren AC (2000) Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am J Med Genet 93:58–66. doi:10.1002/1096-8628(20000703)93:1<58:AID-AJMG10>3.0.CO;2-L

    Article  PubMed  CAS  Google Scholar 

  15. Chen C, Ma X, Zhong M, Yu Z (2010) Extremely low-frequency electromagnetic fields exposure and female breast cancer risk: a meta-analysis based on 24338 cases and 60628 controls. Breast Cancer Res Treat 123:569–576. doi:10.1007/s10549-010-0782-6

    Article  PubMed  Google Scholar 

  16. Ma X, Chen C, Xiong H, Fan J, Li Y, Lin H, Xu R, Huang G, Xu B (2010) No association between SOD2 Val16Ala polymorphism and breast cancer susceptibility: a meta-analysis based on 9,710 cases and 11,041 controls. Breast Cancer Res Treat 122:509–514. doi:10.1007/s10549-009-0725-2

    Article  PubMed  CAS  Google Scholar 

  17. Ma X, Chen C, Xiong H, Li Y (2010) Transforming growth factorbeta1 L10P variant plays an active role on the breast cancer susceptibility in Caucasian: evidence from 10,392 cases and 11,697 controls. Breast Cancer Res Treat 124:453–457. doi:10.1007/s10549-010-0843-x

    Article  PubMed  CAS  Google Scholar 

  18. Ma X, Qi X, Chen C, Lin H, Xiong H, Li Y, Jiang J (2010) Association between CYP19 polymorphisms and breast cancer risk: results from 10,592 cases and 11,720 controls. Breast Cancer Res Treat 122:495–501. doi:10.1007/s10549-009-0693-6

    Article  PubMed  CAS  Google Scholar 

  19. Sergentanis TN, Economopoulos KP (2010) Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis comprising 9,911 cases and 11,171 controls. Mol Biol Rep. doi:10.1007/s11033-010-0639-4

  20. Lehmann DJ, Schuur M, Warden DR, Hammond N, Belbin O, Kolsch H, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, Morris CM, Barker R, Coto E, Alvarez V, Deloukas P, Mateo I, Gwilliam R, Combarros O, Arias-Vasquez A, Aulchenko YS, Ikram MA, Breteler MM, van Duijn CM, Oulhaj A, Heun R, Cortina-Borja M, Morgan K, Robson K, Smith AD (2010) Transferrin and HFE genes interact in Alzheimer’s disease risk: the Epistasis Project. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2010.07.018

  21. Correia AP, Pinto JP, Dias V, Mascarenhas C, Almeida S, Porto G (2009) CAT53 and HFE alleles in Alzheimer’s disease: a putative protective role of the C282Y HFE mutation. Neurosci Lett 457:129–132. doi:10.1016/j.neulet.2009.03.088

    Article  PubMed  CAS  Google Scholar 

  22. Li H, Wetten S, Li L, St Jean P, Upmanyu R, Surh L, Hosford D, Barnes M, Briley J, Borrie M (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 65:45

    Article  PubMed  Google Scholar 

  23. Percy M, Moalem S, Garcia A, Somerville MJ, Hicks M, Andrews D, Azad A, Schwarz P, Beheshti Zavareh R, Birkan R, Choo C, Chow V, Dhaliwal S, Duda V, Kupferschmidt AL, Lam K, Lightman D, Machalek K, Mar W, Nguyen F, Rytwinski PJ, Svara E, Tran M, Wheeler K, Yeung L, Zanibbi K, Zener R, Ziraldo M, Freedman M (2008) Involvement of ApoE E4 and H63D in sporadic Alzheimer’s disease in a folate-supplemented Ontario population. J Alzheimers Dis 14:69–84

    PubMed  CAS  Google Scholar 

  24. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA (2007) GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 54:713–720. doi:10.1016/j.neuron.2007.05.022

    Article  PubMed  CAS  Google Scholar 

  25. Blazquez L, De Juan D, Ruiz-Martinez J, Emparanza JI, Saenz A, Otaegui D, Sistiaga A, Martinez-Lage P, Lamet I, Samaranch L, Buiza C, Etxeberria I, Arriola E, Cuadrado E, Urdaneta E, Yanguas J, Lopez de Munain A (2007) Genes related to iron metabolism and susceptibility to Alzheimer’s disease in Basque population. Neurobiol Aging 28:1941–1943. doi:10.1016/j.neurobiolaging.2006.08.009

    Article  PubMed  CAS  Google Scholar 

  26. Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, Oliveira C (2006) Association of HFE common mutations with Parkinson’s disease, Alzheimer’s disease and mild cognitive impairment in a Portuguese cohort. BMC Neurol 6:24. doi:10.1186/1471-2377-6-24

    Article  PubMed  Google Scholar 

  27. Berlin D, Chong G, Chertkow H, Bergman H, Phillips N, Schipper H (2004) Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI. Neurobiol Aging 25:465–474

    Article  PubMed  CAS  Google Scholar 

  28. Candore G, Licastro F, Chiappelli M, Franceschi C, Lio D, Balistreri CR, Piazza G, Colonna-Romano G, Grimaldi LM, Caruso C (2003) Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer’s disease patients from Northern Italy. Mech Ageing Dev 124:525–528. doi:10.1016/S0047-6374(03)00031-9

    Article  PubMed  CAS  Google Scholar 

  29. Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, Schmitt FA, Markesbery WR (2003) Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet 119B:48–53. doi:10.1002/ajmg.b.10069

    Article  PubMed  Google Scholar 

  30. Lleo A, Blesa R, Angelopoulos C, Pastor-Rubio P, Villa M, Oliva R, Bufill E (2002) Transferrin C2 allele, haemochromatosis gene mutations, and risk for Alzheimer’s disease. J Neurol Neurosurg Psychiatry 72:820–821

    Article  PubMed  CAS  Google Scholar 

  31. Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A, Tagliabue J, Annoni G, Vergani C (2001) The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease. Neurobiol Aging 22:563–568

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr Kauwe from Department of Biology, Brigham Young University, for providing us the detailed information about their study; Dr Lehmann from Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Physiology, Anatomy and Genetics, Oxford, UK, and Dr Ibrahim from Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands, for interpreting the overlapping dada via e-mail during the manuscript writing.

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Authors and Affiliations

  1. Department of Neurology, Fuzhou General Hospital, No.156 Xi’erhuan North Road, Fuzhou, 350025, China

    Min Lin, Lin Zhao, Jian-xin Ye, Lei Wu & Hang Lin

  2. Department of Neurology, Chengdu Military General Hospital, Chengdu, 610083, China

    Jin Fan

  3. Department of Neurology, Jinling Hospital, Nanjing, 210002, China

    Xue-Gan Lian

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  1. Min Lin
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Correspondence to Min Lin or Hang Lin.

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Min Lin and Lin Zhao contributed equally to this article.

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Lin, M., Zhao, L., Fan, J. et al. Association between HFE polymorphisms and susceptibility to Alzheimer’s disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls. Mol Biol Rep 39, 3089–3095 (2012). https://doi.org/10.1007/s11033-011-1072-z

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