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-€4 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.