Human α2-macroglobulin: genotype–phenotype relation

A pentanucleotide deletion polymorphism in the gene of α2-macrolgobulin (α2-M) is suggested to be associated with late-onset Alzheimer’s disease (AD), though controversial results have been reported. The underlying assumption is that the intronic pentanucleotide deletion may affect the biological function and quantity of the inhibitor and thus contribute to the AD pathology. In the present study we have analyzed the distribution of the deletion polymorphism within a group of 227 healthy Caucasians. In parallel studies, we determined the plasma concentrations of total and transformed α2-M. A strong correlation of the total concentration of α2-M with age was ascertained (rs = −0.54, P < 0.001). However, no significant correlation between age and the genotypes (P = 0.68) was detected, and no statistically significant effect of the genotype on the concentrations of total and transformed α2-M was found (P = 0.49 and 0.96, respectively). A significant correlation was observed between total and transformed α2-M in the genotype groups Ins/Ins (rs = 0.56, P < 0.001) and Ins/Del (rs = 0.35, P < 0.004). Furthermore, in the entire data set, a significantly elevated concentration of total α2-M was found in females as compared to males (P = 0.003). There was a slight but nonsignificant difference in the genotype distributions between males and females (P = 0.14). To test the proposed existence of genotype-specific alterations of functional properties of α2-M, we isolated α2-M from the plasma of carriers with different genetic background and analyzed the α2-M subunit structure as well as the binding of the inhibitor to growth factors/cytokines, to amyloid-β and to the receptor. The experiments failed to reveal any genotype-specific functional alterations of the α2-M. The absence of abnormalities in α2-M mRNA and protein suggests that the α2-M deletion polymorphism is probably not associated with functional deficiencies important in AD pathology. However, it can be speculated that the observed general age-related α2-M deficiency may lead to accelerated accumulation of amyloid-β, which might be relevant to AD pathology.