Genetic association of an α2-macroglobulin (Val1000Ile) polymorphism and Alzheimer's disease

A. Liao, R. M. Nitsch, S. M. Greenberg, U. Finckh, D. Blacker, M. Albert, G. W. Rebeck, T. Gomez-Isla, A. Clatworthy, G. Binetti, C. Hock, T. Mueller-Thomsen, U. Mann, K. Zuchowski, U. Beisiegel, H. Staehelin, J. H. Growdon, R. E. Tanzi, B. T. Hyman

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Abstract

α2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid β (Aβ) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P <0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P <0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P <0.001). The presence of the G allele was associated with an increase in Aβ burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Original languageEnglish
Pages (from-to)1953-1956
Number of pages4
JournalHuman Molecular Genetics
Volume7
Issue number12
DOIs
Publication statusPublished - Nov 1998

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ASJC Scopus subject areas

  • Genetics

Cite this

Liao, A., Nitsch, R. M., Greenberg, S. M., Finckh, U., Blacker, D., Albert, M., Rebeck, G. W., Gomez-Isla, T., Clatworthy, A., Binetti, G., Hock, C., Mueller-Thomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J. H., Tanzi, R. E., & Hyman, B. T. (1998). Genetic association of an α2-macroglobulin (Val1000Ile) polymorphism and Alzheimer's disease. Human Molecular Genetics, 7(12), 1953-1956. https://doi.org/10.1093/hmg/7.12.1953