Synergistic Epistasis of Paraoxonase 1 (rs662 and rs85460) and Apolipoprotein E4 Genes in Pathogenesis of Alzheimer’s Disease and Vascular Dementia

Abstract

Genetic polymorphism and epistasis play a role in etiopathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). In this case-control study, a total of 241 patients were included in the study to see the effect of paraoxonase 1 (PON1; rs662 and rs85460) and apolipoprotein E (ApoE) genes in altering the odds of having AD and VaD along with serum PON and lipid profile. The presence of at least 1 variant allele of rs662, but not rs85460, increased the risk of having AD by 1.8-fold (95% confidence interval [CI]: 0.97-3.40) and VaD by 3.09-fold (95% CI: 1.4-6.9). The interaction between PON1 genes (rs662 and rs85460) and ApoE genes showed synergistic epistasis in altering the odds of significantly having both AD and VaD. On the other hand, low serum level of high-density lipoprotein and low level of serum PON activity were found associated significantly (P ≤ .001 in both cases) only in patients with VaD as compared to healthy control.

Serum paraoxonase and arylesterase activities of paraoxonase‐1 (PON‐1), mild cognitive impairment, and 2‐year conversion to dementia: A pilot study

“…Although our previous work was, to the best of our knowledge, the only one to measure both serum activities in relation to the diagnosis of dementia, we found an overall consistency of the results with other large studies dealing with this topic (Wehr et al 2009;Erlich et al 2012;Bednarska-Makaruk et al 2013). While arylesterase was repeatedly found to be associated with a LOAD diagnosis, paraoxonase turned out to be related with VAD in other two works (Paragh et al 2002;Alam et al 2014). The most extensively explored PON-1 coding single nucleotide polymorphisms (i.e., rs662 and rs854560), which strongly influence paraoxonase rather than arylesterase activity (Tang et al 2012), consistently failed to be associated with the susceptibility to develop LOAD based on the available published studies (Pi et al 2012).…”

Organophosphate pesticides and PON1 L55M in Parkinson's disease progression

“…Which of these functions contribute to cognitive decline in PD or both remains unclear. Though multiple independent investigations associate PON1 with AD and vascular dementia, both by examining genomic variation and with enzyme activity (Alam et al 2014). A recent meta-analysis of 69 studies associated L55M, as one of four polymorphisms apart from APOE, with vascular dementia (Zhub et al 2015).…”

Genetics of vascular dementia – review from the ICVD working group

“…However, there was no difference in risk for VaD between ε2 and ε3 allele carriers nor in the APOE promoter T-427C [2]. Two polymorphisms (Q192R and L55M) of PON1 were associated with a higher risk of VaD in Indian and French populations [26–28], but these findings for Q192R were not confirmed in two other studies on European populations [29, 30]. Several genes related to inflammation have also been related to VaD, including two polymorphisms in the TNF-α in Europeans [31] and Asians [32].…”