Therapeutic Response to Paroxetine in Major Depressive Disorder Predicted by DNA Methylation
Therapeutic Response to Paroxetine in Major Depressive Disorder Predicted by DNA Methylation
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DOI：
10.1159/000480512
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发表时间：
2017-11
影响因子：
3.2
通讯作者：
Naohiro Takeuchi;S. Nonen;Masaki Kato;M. Wakeno;Y. Takekita;T. Kinoshita;F. Kugawa
中科院分区：
文献类型：
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作者：
Naohiro Takeuchi;S. Nonen;Masaki Kato;M. Wakeno;Y. Takekita;T. Kinoshita;F. Kugawa
背景：抗抑郁药的疗效因遗传和环境因素而异。大约30%的重性抑郁症（MDD）患者对抗抑郁药如帕罗西汀（一种选择性5-羟色胺再摄取抑制剂（SSRI））无显著反应。然而，这种现象背后的生物学机制大多是未知的。在这里，我们研究了患者的表观遗传背景在SSRI疗效中的作用。研究方法：使用Infinium HumanMethylation 450 BeadChip对日本MDD患者的外周血进行全基因组DNA甲基化分析。结果如下：我们比较了10名对帕罗西汀（BR）反应最好的患者与10名反应最差的患者（WR）的结果，发现623个CpG位点的DNA甲基化水平差异>10%。其中，218个位点在BR和WR之间名义上存在显著性差异（p < 0.05），2个位点（cg 00594917和cg 07260927）在错误发现率（FDR）校正后存在显著性差异（q < 0.05）。甲基化差异在cg 00594917处最大，位于PPFIA 4基因的第一个外显子，该基因编码脂蛋白-α（p = 0.00012）。PPFIA 4基因23个CpG位点的分层聚类分析区分了BR和WR，除了1例WR患者。cg 07260927位点位于硫酸肝素-葡糖胺3-磺基转移酶1（HS 3ST 1）基因的5′UTR（p = 0.00013）。HS 3ST 1基因28个CpG位点的聚类分析将BR和WR区分开来，除了1例WR和2例BR患者。结论：我们的研究结果表明，患者在特定基因（如PPFIA 4和HS 3ST 1）的DNA甲基化谱与帕罗西汀治疗反应的个体差异相关。
Background: Antidepressants have variable therapeutic effects, depending on genetic and environmental factors. Approximately 30% of major depressive disorder (MDD) patients do not respond significantly to antidepressants such as paroxetine, a selective serotonin reuptake inhibitor (SSRI). However, the biological mechanisms behind this phenomenon are mostly unknown. Here, we examined the role of patients' epigenetic background in SSRI efficacy. Methods: Genome-wide DNA methylation analysis of the peripheral blood of Japanese MDD patients was performed by using the Infinium HumanMethylation450 BeadChip. Results: We compared the results of the 10 patients who best responded to paroxetine (BR) with the 10 worst responders (WR), and found 623 CpG sites with a >10% difference in DNA methylation level. Among them, 218 sites were nominally significant between BR and WR (p < 0.05), and 2 sites (cg00594917 and cg07260927) were significantly different after false discovery rate (FDR) correction (q < 0.05). The methylation difference was greatest at cg00594917, located in the first exon of the PPFIA4 gene, which codes for liprin-α (p = 0.00012). Hierarchical cluster analysis of 23 CpG sites in the PPFIA4 gene distinguished BR and WR, except for 1 WR patient. The cg07260927 site was located in the 5′UTR of the heparin sulfate-glucosamine 3-sulfotransferase 1 (HS3ST1) gene (p = 0.00013). Hierarchical cluster analysis of 28 CpG sites in HS3ST1 distinguished BR and WR, except for 1 WR and 2 BR patients. Conclusion: Our results suggest that patients' DNA methylation profile at specific genes such as PPFIA4 and HS3ST1 is associated with individual variations in therapeutic responses to paroxetine.