Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression
Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression
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DOI：
10.1038/s41386-019-0319-6
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发表时间：
2019-04-01
影响因子：
7.6
通讯作者：
Grabe, Hans J.
中科院分区：
文献类型：
--
作者：
Klinger-Koenig, Johanna;Hertel, Johannes;Grabe, Hans J.
FKBP5基因的DNA甲基化被认为改变了FKBP5的表达，从而改变了FK506结合蛋白51的合成，FK506结合蛋白51是糖皮质激素受体信号的基因组负反馈环的中心元件。本研究旨在复制和扩展先前报道的FKBP5基因、儿童期虐待和抑郁对FKBP5基因内含子7的5个CpG位点甲基化水平的影响。除了单核苷酸多态(SNP)rs1360780外，还研究了FKBP5甲基化与其他22个未连锁的FKBP5单核苷酸多态之间的关联，以及FKBP5甲基化水平和转录水平之间的关联。在波美拉尼亚健康研究(SHIP)的3,965名受试者中，发现rs1360780的TT等位基因携带者(OR=0.975，p=0.005)和目前抑郁的受试者(OR=0.995，p=0.005)的甲基化水平降低。此外，观察到两个尚未描述的SNPs(rs6910300，rs7771727)对甲基化水平的影响。然而，先前研究中观察到的儿童期虐待和终生严重抑郁障碍的主要和相互作用的影响不能重复。最后，FKBP5甲基化水平与全血中FKBP5转录水平无关。因此，本研究验证了FKBP5基因与抑郁状态对内含子7中5个CpG位点甲基化水平的影响。然而，这5个CpG位点的FKBP5甲基化不能被确认为儿童虐待或终生抑郁的生物学长期影响的有价值的临床生物标志物。
DNA methylation of the FKBP5 gene is assumed to alter FKBP5 expression and hence the synthesis of the FK506 binding protein 51, a central element of a genomic negative feedback loop for glucocorticoid receptor signaling. The present study aimed to replicate and extend previously reported influences of FKBP5 genotypes, childhood maltreatment and depression on methylation levels of five CpG sites in intron 7 of the FKBP5 gene in a large population-based sample. Besides the single nucleotide polymorphism (SNP) rs1360780, associations of the FKBP5 methylation with 22 other, unlinked FKBP5 SNPs as well as associations between FKBP5 methylation levels and transcription levels were investigated. Using whole-blood methylation of 3965 subjects of the Study of Health in Pomerania (SHIP) reduced methylation levels in TT allele carriers of rs1360780 (OR = 0.975, p =.005) and currently depressed subjects (OR = 0.995, p = 0.005) were found. Further, an impact of two yet undescribed SNPs (rs6910300, rs7771727) on methylation levels was observed. However, main and interactive effects for childhood maltreatment and lifetime major depressive disorder observed in previous studies could not be replicated. Finally, FKBP5 methylation levels were not related to FKBP5 transcription levels in whole blood. Thus, the present study verified the associations of FKBP5 genotypes and state depression on the FKBP5 methylation levels of five CpG sites in intron 7. However, FKBP5 methylation of these five CpG sites could not be validated as a valuable clinical biomarker for biological long-term effects of childhood maltreatment or lifetime depression.