The synergistic risk effect of apolipoprotein [epsilon]4 and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) haplotype for Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial disease with the contribution of several genes and polymorphisms to its development. Among these genes, the APOE[straight epsilon]4 is the best known risk factor for AD. Methylation is associated with APOE expression and AD development. Recently, we found an association of the TGG haplotype in the DNMT3B gene, one of the catalyst enzyme for methylation, with AD. Therefore, the objective of the study was to investigate whether APOE[straight epsilon]4 and TGG haplotype have an synergistic effect on AD. The sample was composed of 212 Caucasian individuals (108 healthy controls and 104 with AD by NINCDS-ADRDA and DSM-IV-TR criteria) from southern Brazil. The genetic analyses were performed by real time PCR for TaqMan assay. Multivariate logistic regression was performed categorizing groups according to presence of APOE[straight epsilon]4 and/or TGG haplotype as an independent variable for outcome AD. The presence of TGG haplotype plus the allele APOE[straight epsilon]4 were strongly associated with AD [OR 11.13; 95 % CI (4.25-29.16); P < 0.001]. This association had a higher risk than each risk factor alone. We found a strong association of the interaction of DNMT3B gene with the APOE[straight epsilon]4 in this sample of AD patients. The presence of TGG haplotype and APOE[straight epsilon]4 significantly increased the risk of developing the disease, showing an synergistic effect.