American Journal of Epidemiology Advance Access originally published online on July 20, 2005
American Journal of Epidemiology 2005 162(4):305-317; doi:10.1093/aje/kwi202
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
META-ANALYSIS |
Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer's Disease
1 The Oxford Project to Investigate Memory and Ageing (OPTIMA), Department of Pharmacology, University of Oxford, Oxford, United Kingdom
2 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, London, United Kingdom
3 Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, the Netherlands
4 Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
5 Care of the Elderly, Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, United Kingdom
Correspondence to D. J. Lehmann, University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, United Kingdom (e-mail: donald.lehmann{at}pharm.ox.ac.uk).
Apolipoprotein E 
4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion (I)/deletion (D) polymorphism (indel) of the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age, ethnic group, and carrier status of the apolipoprotein E 4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction warrants further investigation.
Alzheimer disease; heterogeneity; meta-analysis
Abbreviations: ACE, angiotensin I-converting enzyme (protein); ACE, angiotensin I-converting enzyme (gene); APOE*4, apolipoprotein E
4 (allele)
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Zou, T. Maeda, A. Watanabe, J. Liu, S. Liu, R. Oba, Y.-i. Satoh, H. Komano, and M. Michikawa A{beta}42-to-A{beta}40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme J. Biol. Chem., November 13, 2009; 284(46): 31914 - 31920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A V September, J Cook, C J Handley, L van der Merwe, M P Schwellnus, and M Collins Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations Br. J. Sports Med., May 1, 2009; 43(5): 357 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Hua Liu, Ming Liu, Wei Li, Bo Wu, S.-h. Zhang, Yuan Fang, and Yi Wang Association of ACE I/D Gene Polymorphism With Vascular Dementia: A Meta-Analysis J Geriatr Psychiatry Neurol, March 1, 2009; 22(1): 10 - 22. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Zintzaras, G. Raman, G. Kitsios, and J. Lau Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphic Variant as a Marker of Coronary Artery Disease: A Meta-analysis Arch Intern Med, May 26, 2008; 168(10): 1077 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Hajjar, M. Keown, P. Lewis, and A. Almor Angiotensin Converting Enzyme Inhibitors and Cognitive and Functional Decline in Patients with Alzheimer's Disease: An Observational Study American Journal of Alzheimer's Disease and Other Dementias, March 1, 2008; 23(1): 77 - 83. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Zou, H. Yamaguchi, H. Akatsu, T. Sakamoto, M. Ko, K. Mizoguchi, J.-S. Gong, W. Yu, T. Yamamoto, K. Kosaka, et al. Angiotensin-Converting Enzyme Converts Amyloid {beta}-Protein 1 42 (A{beta}1 42) to A{beta}1 40, and Its Inhibition Enhances Brain A{beta} Deposition J. Neurosci., August 8, 2007; 27(32): 8628 - 8635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Ellul, N Archer, C M L Foy, M Poppe, H Boothby, H Nicholas, R G Brown, and S Lovestone The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration J. Neurol. Neurosurg. Psychiatry, March 1, 2007; 78(3): 233 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Eckman, S. K. Adams, F. J. Troendle, B. A. Stodola, M. A. Kahn, A. H. Fauq, H. D. Xiao, K. E. Bernstein, and C. B. Eckman Regulation of Steady-state beta-Amyloid Levels in the Brain by Neprilysin and Endothelin-converting Enzyme but Not Angiotensin-converting Enzyme J. Biol. Chem., October 13, 2006; 281(41): 30471 - 30478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F.A. Sayed-Tabatabaei, B.A. Oostra, A. Isaacs, C.M. van Duijn, and J.C.M. Witteman ACE Polymorphisms Circ. Res., May 12, 2006; 98(9): 1123 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Hemming and D. J. Selkoe Amyloid {beta}-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor J. Biol. Chem., November 11, 2005; 280(45): 37644 - 37650. [Abstract] [Full Text] [PDF]
|
|