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    • We further correlated OPRK and OPRM methylation levels

    2019-09-12

    We further correlated OPRK1 and OPRM1 methylation levels with individual characteristics in Xinjiang Han and Uygur controls. Partial correlation analyses showed that OPRK1 methylation was positively correlated with age in Uygur male controls (r=0.72, p=0.001, adjusted by body mass index CJ-42794 mass (BMI), glucose, triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C)). Our results also found that OPRM1 CpG2-4 methylation was negatively correlated with HDL-C level in Han male controls (r=−0.50, p=0.04, adjusted by age, BMI, glucose, TG, TC and low density LDL-C). Further cell transfection experiment showed that luciferase reporter gene activity was significantly enhanced by OPRK1 and OPRM1 promoter fragments (Fig. 4, OPRK1: fold change=2.248, p=0.008; OPRM1: fold change=2.616, p=0.003).
    Discussion In the current study, we tested the association of OPRK1 and OPRM1 promoter methylation with MCI in two Xinjiang populations, Han and Uygur. Our result showed that OPRK1 hypermethylation was a risk factor of MCI only in Xinjiang Han females. In addition, OPRM1 CpG1 hymethylation was associated with MCI in Xinjiang Uygur population, while OPRM1 CpG2-4 hypomethylation was associated with MCI in Xinjiang Han population. Opioid receptors were abundant in hippocampus which is important for learning and memory [22]. Opioid receptors were abundant in hippocampus which is important for learning and memory [22], [23]. Moreover, opioid receptors activation was involved in AD pathologies through protecting CJ-42794 mass and inhibiting the formation and toxicity of Aβ [24], [25]. OPRK1 agonists were shown to restore the Aβ-induced deterioration of cognition in mouse model [26]. Previous evidence also revealed that opioid receptor kappa was decreased in AD hippocampus [27]. In the present study, OPRK1 promoter was hypermethylated in female Xinjiang Han MCI, which was similar with the previous findings in AD [16]. This suggested that OPRK1 methylation was an early event in the development of AD, especially for Xinjiang Han females. OPRM1 antagonist could provide protective function in spatial memory deficit induced by cannabis [28]. Others suggested that morphine, functioned through OPRM1, would alleviate the impairment produced by Aβ in primary neuronal cell model and rat in vivo [29]. OPRM1 methylation was observed to be associated with alcohol dependence and opioid addiction [17], [30]. Moreover, heroin addicts were found to have an ethnic difference in the OPRM1 methylation levels [18]. In the present study, OPRM1 CpG1was hypermethylated in Uygur MCI and ethnic difference was observed in MCI patients while OPRM1 CpG2-4 showed hypomethylation in Han female MCI than controls. Thus, the exact mechanisms of OPRM1methylation in MCI should be further explored. Our study showed that OPRK1 and OPRM1 were more methylated in Xinjiang (Northwest China) than Zhejiang (Southeast China) Han Chinese healthy controls. The above region-related methylation changes of OPRK1 and OPRM1 suggested that their DNA methylation could be altered by environmental factors [31]. Xinjiang province is located in the Northwestern China, and seed coat is a multi-ethnic-populated region where Han and Uygur Chinese consist of two largest Xinjiang ethnicities [32]. The genetic backgrounds, lifestyles and diets are distinct between the two populations [33]. Epidemiological study revealed that the prevalence of AD in Uygur and Han populations was 3.24% and 4.19%, respectively [33]. Zhejiang province with simple ethnic composition was in the Southeastern China [34]. As shown in Fig. 3, Xinjiang is located in inland region and Zhejiang was in the east coast of China. Hence, distinct geographic locations rendered various external factors including climates, diet habits and lifestyles which may contribute to different DNA methylation outcomes of the two genes. Our results also showed that Xinjiang Han male controls tended to have higher OPRK1 methylation levels than female controls. The prevalence of MCI in males was higher than females [35]. Male MCI had a higher rate of progression to AD [36], and a higher mortality risk [37]. Female MCI benefited more through cognition training than male MCI [38]. The gender-related difference in OPRK1 methylation may help elaborate the gender difference in the susceptibility and prognosis of MCI. Interestingly, we found OPRK1 methylation was significantly correlated with aging in Xinjiang Uygur male controls. Given its higher methylation in MCI, Uygur males might face a higher risk of MCI along with aging.