Pharmacogenetic Study on the Impact of Rivastigmine Concerning Genetic Variants of A2M and IL-6 Genes on Iranian Alzheimer's Patients.

Abstract

Alzheimer's disease (AD) is a polygenic and multifactorial disease with a complex inheritance caused by the formation of amyloid plaques and neurofibrillary tangles in the brain. Increasing evidence indicates that many genes including interleukin-6 (IL-6) and alpha 2-macroglobulin (A2M) may contribute to the pathogenesis of AD. The A2M gene encodes α2-macroglobulin which specifically binds with the beta-amyloid peptides and prevents fibril formation. Protein of the IL-6 gene linked to beta-amyloid (βA) aggregation was detected in βA plaques in the brain of AD patients. The aim of the present study is to investigate the relationship of the IL-6 and A2M gene polymorphisms with AD and also the impact of rivastigmine on AD patients regarding their genotypes on IL-6 and A2M genes in 150 Iranian AD patients under rivastigmine therapy and 150 matched healthy controls. The results indicated that IL-6 G and C alleles had significant positive and negative association with AD, respectively, (P = 0.0001, relative risks (RR) = 1.39) and frequency of AD patients carrying IL-6 GG genotype was significantly in higher proportion in familial Alzheimer's disease (FAD) patients compared to controls (P = 0.02, RR = 2.25), and the IL-6 CC genotype was significantly protective against AD (P = 0.0003, RR = 0.65). Genotype analysis of A2M gene showed a significant positive correlation between A2M AA genotype and the AD patients (sporadic Alzheimer's disease (SAD) and FAD) (P = 0.001, RR = 1.56), proposing it as a possible risk factor for AD. Drug response from pharmacogenetic viewpoint after 3-year follow-up of AD patients and Clinical Dementia Rating (CDR) analysis demonstrated that AD patients carrying bigenic genotype IL-6 CC-A2M AG (ΔCDR = 4.5) and male patients with IL-6 CC genotype (ΔCDR = 3.83) provided the best response and the A2M GG genotype (ΔCDR = 7.97) and bigenic genotype IL-6 GG-A2M GG (ΔCDR = 8.5) conferred the worst response to the rivastigmine, suggesting likely involvement of genotype-specific response to rivastigmine therapy in AD patients. The results also propose that in view of the fact that C and G alleles created by nucleotide changes in the promoter region of IL-6 gene and this may affect the expression of the IL-6 gene and, hence, susceptible and protective role of GG and CC genotype in AD might be caused by higher and lower expression of IL-6 cytokine, respectively.