Increased Risk for Alzheimer Disease With the Interaction of MPO and A2M Polymorphisms

Background The genes encoding myeloperoxidase ( MPO ) and α 2 -macroglobulin ( A2M ) are involved in molecular pathways leading to β-amyloid deposition. Two polymorphic sites in these genes ( MPO-G/A and A2M-Ile/Val ) have been associated with Alzheimer disease (AD), but conflicting findings have been reported in populations with different ethnic backgrounds. Objectives To study the association of MPO-G/A and A2M-Ile/Val polymorphisms with sporadic AD and to investigate the interactions among the MPO , A2M , and apolipoprotein E ( APOE ) gene polymorphisms in determining the risk of the development of AD. Design Case-control study. Setting Referral center for AD in Calabria, southern Italy. Participants One hundred forty-eight patients with sporadic AD and 158 healthy control subjects. Results The MPO-G and A2M-Val alleles were found more frequently in cases than in controls, as were the MPO-G/G and A2M-Val/Val genotypes. The odds ratio (OR) for the MPO-G/G genotype was 1.78 (95% confidence interval [CI], 1.13-2.80); for the A2M-Val/Val genotype, 3.81 (95% CI, 1.66-8.75). The presence of MPO-G/G and A2M-Val/Val genotypes synergistically increased the risk of AD (OR, 25.5; 95% CI, 4.65-139.75). Stratification of cases by sex, age at onset of AD, and APOE-ϵ4 status did not show significant differences in the distribution of MPO or A2M polymorphisms. Conclusions The MPO and A2M polymorphisms are associated with sporadic AD in southern Italy. Moreover, a genomic interaction between these polymorphisms increases the risk of the development of AD.