Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity
Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity
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DOI：
10.1038/tp.2017.133
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发表时间：
2017-07-04
影响因子：
6.8
通讯作者：
Hesse, S.
中科院分区：
文献类型：
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作者：
Drabe, M.;Rullmann, M.;Hesse, S.
编码人血清素转运蛋白（5-HTT）的SLC 6A 4基因（5-HTTLPR）启动子区的多态性与调节对压力相关精神病理学的易感性有关，并对人体体内5-HTT的利用率具有调节功能。然而，关于5-HTTLPR和体内5-HTT可用性之间的直接关系的数据一直不一致。其他因素如5-HTTLPR的表观遗传修饰可能有助于这种关联。这在肥胖症的背景下特别令人感兴趣，因为先前已经报道了与5-HTTLPR超甲基化的关联。在此，我们检验了一个假设，即在一组30名肥胖者中，14个胞嘧啶磷酸鸟嘌呤（CpG）5-HTTLPR位点的甲基化率、体内中心5-HTT可用性（用[C-11] DASB正电子发射断层扫描（PET）测量）和体重指数（BMI）相关。（年龄：36 +/-3 10岁，BMI 435 kg/m2）和14名正常体重对照（年龄：36 +/-7岁，BMI < 25 kg/m2）。5-HTTLPR甲基化和BMI总体上没有显著相关性，但是，当单独分析时，5-HTTLPR甲基化率的位点特异性升高与前额叶皮质（PFC）区域5-HTT可用性降低显著相关，特别是在肥胖组中。这种关联独立于功能性5-HTTLPR等位基因变异。此外，负相关数据表明，CpG 10相关的5-HTT的可用性决定了肥胖的奖励敏感性水平。总之，我们的研究结果表明，表观遗传机制，而不是5-HTTLPR单独影响体内5-HTT的可用性，主要是在奖励处理中具有关键作用的区域，这可能会对肥胖表型的进展产生影响。
A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [C-11] DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36 +/- 3 10 years, BMI435 kg/m(2)) and 14 normal-weight controls (age 36 +/- 7 years, BMI < 25 kg/m(2)). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.