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    • Mild cognitive impairment MCI is a clinical

    2019-09-10

    Mild cognitive impairment (MCI) is a clinical transitional stage between normal aging and Alzheimer disease (AD) [1]. Approximate 15–30% MCI patients convert to AD annually. Although many efforts have been taken to prevent the conversion from MCI to AD [2], [3], there are few biomarkers to predict the progression of MCI. MCI is a complex and multifactorial disease. The interaction between epigenetics and environment contributes to the development of MCI [4], [5], [6]. DNA methylation, an important epigenetic modification, is known to regulate gene expression. Accumulating pieces of evidence have shown an involvement of aberrant DNA methylation events in β-amyloid-induced cognitive impairment [7], hippocampus function, and synaptic plasticity [6]. DNA methyltransferase 3A, catalyzing methylation modification, was reported to be associated with progressive cognitive decline in MCI [4]. Recently, several lines of evidence demonstrated that DNA methylation played a crucial role in the pathologies of MCI [8], [9], [10]. Identification of new aberrantly methylated genes might explain pathogenesis of MCI. Opioid receptor kappa 1 (OPRK1) and opioid receptor mu 1 (OPRM1) were widely studied opioid receptors, which were broadly expressed in brain. Both receptors were able to regulate the function of learning and memory [11], [12]. OPRK1 was associated with cognitive deficits induced by long term stress as well as osteoarthritis pain [13], [14]. Besides, OPRM1 antagonist was shown to play an important role in morphine induced memory impairment [15]. Interestingly, hypermethylated OPRK1 and OPRM1 were previously found to be associated with AD [16], alcohol dependence and opioid addiction [17], [18]. In the present study, we focused on the methylation of the two genes with the risk of MCI.
    Methods and subjects
    Results In the present study, we selected the CpG islands in the 5′ flanking regions of OPRK1 and OPRM1 (Fig. 1). The regions were also overlapped with DNase cluster and transcription factor melatonin receptor agonist (Fig. 1). We also found significant correlations among the methylation levels of three OPRK1 CpGs in Xinjiang Uygur and Han healthy controls (Fig. 1, Uygur: r>0.56, p<0.05; Han: r>0.80, p<0.05). Thus, OPRK1 mean methylation level was used for the subsequent association tests. In contrast, OPRM1 CpG1 methylation levels were not significantly correlated with the methylation levels of other OPRM1 CpG sites in Xinjiang Uygur controls (p>0.05). Therefore, both OPRM1 CpG1 and CpG2-4 methylation levels were used in the following association tests. No significant associations were observed between OPRK1 methylation and MCI in both Xinjiang Han and Uygur populations (p>0.05, Fig. 2). A breakdown analysis by gender showed that OPRK1 promoter was significantly hypermethylated in female Han MCI patients (p=0.01, Fig. 2). No significant difference of OPRK1 methylation between Xinjiang Han and Uygur populations. As melatonin receptor agonist for OPRM1 methylation, compared to healthy controls, OPRM1 CpG1 methylation levels were higher in Xinjiang Uygur MCI (p=1.00E−04, Fig. 2), in contrast that OPRM1 CpG2-4 methylation levels were lower in Han MCI (p=2.00E−03, Fig. 2). Subgroup analyses by gender also indicated significant associations between OPRM1 CpG1 hypermethylation and MCI in both genders (male: p=0.02; female: p=1.00E−03), while the association of CpG2-4 hypomethylation with MCI was only observed in female Xinjiang Han MCI (p=0.05, Fig. 2). We speculated the loss of significance between CpG2-4 and MCI in the male Xinjiang Han might be due to a lack of power in the subgroup test. We also compared the methylation levels of the two genes between Xinjiang and Zhejiang Han controls. Our results showed a significantly higher OPRK1 methylation in Xinjiang Han population (OPRK1: p=0.01, Fig. 3), especially for the males (p=0.0002). There were significantly higher OPRK1 methylation levels in Xinjiang male controls than Xinjiang female controls (p=2.00E−03, Fig. 3). Meanwhile, significantly higher OPRM1 CpG1 and CpG2-4 methylation levels were observed in Xinjiang controls than Zhejiang controls (CpG1: p=1.00E-05; CpG2-4: p=1.00E−13). The same trends were also found in the gender-based comparisons (Fig. 3, all p<1.00E−03).