Lack of association of the alpha2-macroglobulin locus on chromosome 12 in AD.

ABSTRACT

OBJECTIVE: Analysis of AD has revealed that the apolipoprotein E locus (APOE) cannot account for all of the genetic risk associated with AD. Whole genome scanning in AD families suggests that a chromosome 12 locus may contribute significantly to disease development. The alpha2-macroglobulin gene (A2M) has been suggested as a candidate locus for AD based on analysis of familial AD. METHOD: We determined, in 195 neuropathologically verified AD cases and 107 age-matched control subjects, the association of two common polymorphisms in A2M (a pentanucleotide deletion 5' to the bait domain exon, and a valine-1000-isoleucine polymorphism in the thiolester site of the protein). RESULTS: Evidence was observed for linkage disequilibrium between the deletion and Ile1000 polymorphisms. No evidence was observed for an association between the thiolester polymorphism and AD alone or when accounting for the APOE-epsilon4 allele. No alteration in the frequency of the bait domain deletion was observed, although a small excess (4%) of deletion homozygotes was found in the AD group, which were absent in the control population. CONCLUSIONS: The A2M deletion polymorphism at most accounts for a small fraction of the genetic contribution toward AD, and this is small compared with APOE. Furthermore, reverse transcriptase PCR of A2M RNA from the brains of patients homozygous for the deletion polymorphism showed that the bait domain exon still is present in the RNA. This suggests that the A2M deletion polymorphism may be nonfunctional and that the chromosome 12 AD locus is situated elsewhere.