Supplementary Material for: Association Study and Meta-Analysis of Polymorphisms, Methylation Profiles, and Peripheral mRNA Expression of the Serotonin Transporter Gene in Patients with Alzheimer's Disease

Background/Aim: The aim of this study was to elucidate the relationship between Alzheimer's disease (AD) and the serotonin transporter gene (SLC6A4). Methods: AD subjects (n = 43) and controls (n = 47) were recruited and evaluated. In leukocytes, we evaluated two polymorphisms in SLC6A4, the serotonin transporter length polymorphic region (5-HTT-LPR) and rs25531, as well as methylation rates of theSLC6A4 promoter region and the SLC6A4 mRNA expression level. We also performed a meta-analysis to examine the relationship between the frequency of the L allele and the risk of AD. Results: The distributions of 5-HTT-LPR and rs25531 polymorphisms in AD subjects were not different from those of controls. Although the methylation rates in AD subjects were not significantly different from those of controls, the expression level in AD subjects was significantly higher than in controls. Additionally, the expression level in AD subjects was significantly correlated with apathy. Meta-analysis revealed that the L/L genotype significantly reduced the risk of AD, but only in the Caucasian population. Conclusion: Higher SLC6A4 mRNA expression in leukocytes in AD was associated with apathy regardless of SLC6A4 genotypes and methylation rates of the promoter region. The L/L genotype may reduce the risk of AD in the Caucasian population.

背景与目的：本研究旨在阐明阿尔茨海默病（Alzheimer's disease, AD）与5-羟色胺转运体基因（SLC6A4）之间的关联。
方法：本研究招募了43名阿尔茨海默病患者与47名健康对照者并进行评估。我们对白细胞中的SLC6A4基因的两个多态性位点——5-羟色胺转运体长度多态性区域（5-HTT-LPR）及rs25531，以及SLC6A4启动子区域的甲基化水平和SLC6A4的mRNA表达量进行了检测。此外，我们还开展了荟萃分析，以探究L等位基因频率与阿尔茨海默病发病风险之间的关系。
结果：阿尔茨海默病患者中5-HTT-LPR与rs25531多态性的分布与健康对照者无显著差异。尽管阿尔茨海默病患者的甲基化水平与健康对照者无显著差异，但患者的mRNA表达量显著高于对照者。此外，阿尔茨海默病患者的mRNA表达量与淡漠症状显著相关。荟萃分析结果显示，L/L基因型可显著降低阿尔茨海默病的发病风险，但该效应仅在高加索人群中显著。
结论：阿尔茨海默病患者白细胞中更高的SLC6A4 mRNA表达量与淡漠症状相关，且该关联不受SLC6A4基因型及启动子区域甲基化水平的影响。L/L基因型或可降低高加索人群的阿尔茨海默病发病风险。