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Background <p>Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease characterized by subjective cognitive decline and objective evidence of cognitive impairment revealed through neuropsychological examinations. Dopamine receptors play a pivotal role in the modulation of memory and cognitive functions. <i>DRD4</i> is a dopamine receptor gene enriched in memory-related brain regions, modulates synaptic plasticity, and its promoter methylation status. While <i>DRD4</i> promoter methylation is implicated in neurodevelopmental disorders, its role in MCI pathogenesis remains uninvestigated across ethnically diverse populations.</p> Purpose <p>Our study focused on the association between <i>DRD4</i> methylation and MCI in Uygur and Han populations.</p> Patients and methods <p>192 age–sex-matched participants (48 Uygur MCI, 48 Uygur controls, 48 Han MCI, 48 Han controls) were recruited from Xinjiang and Zhejiang, China. MCI diagnosis followed DSM-IV criteria with cognitive assessment (MMSE/MoCA). Peripheral blood DNA underwent bisulfite conversion, followed by pyrosequencing of <i>DRD4</i> promoter CpG sites 1–4 (PyroMark Q24). Group comparisons used independent <i>t</i>-tests with two-way ANOVA for covariate adjustment (age/sex/ethnicity); Pearson/Spearman tests assessed methylation-biomarker correlations. Methylation was measured using bisulfite pyrosequencing.</p> Results <p>Our results indicated that MCI-related hypermethylation was detected in the Uygur (CpG1) and Han (CpG1–3) populations, and subgroup analyses by sex in the Uygur population displayed consistent results, while in the Han subgroup, <i>DRD4</i> hypermethylation was only observed in the male group. Ethnic differences in CpG4 (CpG: cytosine phosphate guanine) in male cases, CpG1 in overall control, and CpG3 in male controls. Regional distinctions were shown between CpG1and CpG4 in the male subgroup. Diverse correlations were observed. CpG1 methylation in the Uygur male control groups, Uygur female case groups, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG4 in Uygur female controls and Han female patients correlated with Glu and age.</p> Conclusion <p>Our findings provide novel insights into <i>DRD4</i> methylation in Uygur and Han populations.</p>

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Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations

  • 期刊论文

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  • 发表日期：

    2025年11月26日

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  • Chunshuang Xu,
  • Guili Liu,
  • Huihui Ji,
  • Qi Yao,
  • Wei Cui,
  • Shujun Xu,
  • Xiaohui Zhou,
  • Jingbo Yu,
  • Qinwen Wang

摘要

Background

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease characterized by subjective cognitive decline and objective evidence of cognitive impairment revealed through neuropsychological examinations. Dopamine receptors play a pivotal role in the modulation of memory and cognitive functions. DRD4 is a dopamine receptor gene enriched in memory-related brain regions, modulates synaptic plasticity, and its promoter methylation status. While DRD4 promoter methylation is implicated in neurodevelopmental disorders, its role in MCI pathogenesis remains uninvestigated across ethnically diverse populations.

Purpose

Our study focused on the association between DRD4 methylation and MCI in Uygur and Han populations.

Patients and methods

192 age–sex-matched participants (48 Uygur MCI, 48 Uygur controls, 48 Han MCI, 48 Han controls) were recruited from Xinjiang and Zhejiang, China. MCI diagnosis followed DSM-IV criteria with cognitive assessment (MMSE/MoCA). Peripheral blood DNA underwent bisulfite conversion, followed by pyrosequencing of DRD4 promoter CpG sites 1–4 (PyroMark Q24). Group comparisons used independent t-tests with two-way ANOVA for covariate adjustment (age/sex/ethnicity); Pearson/Spearman tests assessed methylation-biomarker correlations. Methylation was measured using bisulfite pyrosequencing.

Results

Our results indicated that MCI-related hypermethylation was detected in the Uygur (CpG1) and Han (CpG1–3) populations, and subgroup analyses by sex in the Uygur population displayed consistent results, while in the Han subgroup, DRD4 hypermethylation was only observed in the male group. Ethnic differences in CpG4 (CpG: cytosine phosphate guanine) in male cases, CpG1 in overall control, and CpG3 in male controls. Regional distinctions were shown between CpG1and CpG4 in the male subgroup. Diverse correlations were observed. CpG1 methylation in the Uygur male control groups, Uygur female case groups, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG4 in Uygur female controls and Han female patients correlated with Glu and age.

Conclusion

Our findings provide novel insights into DRD4 methylation in Uygur and Han populations.