Haghighi Fatemeh, Galfalvy Hanga, Chen Sean, Huang Yung-Yu, Cooper Thomas B, Burke Ainsley K, Oquendo Maria A, Mann J John, Sublette M Elizabeth
Department of Psychiatry, James J. Peters Veterans Affairs Medical Center , New York, NY , USA ; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY , USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York, NY , USA.
Department of Psychiatry, Columbia University College of Physicians and Surgeons , New York, NY , USA ; Division of Biostatistics, New York State Psychiatric Institute , New York, NY , USA.
Front Neurol. 2015 Apr 28;6:92. doi: 10.3389/fneur.2015.00092. eCollection 2015.
Polyunsaturated fatty acid (PUFA) status has been associated with neuropsychiatric disorders, including depression and risk of suicide. Long-chain PUFAs (LC-PUFAs) are obtained in the diet or produced by sequential desaturation and elongation of shorter-chain precursor fatty acids linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3). We compared DNA methylation patterns in genes involved in LC-PUFA biosynthesis in major depressive disorder (MDD) with (n = 22) and without (n = 39) history of suicide attempt, and age- and sex-matched healthy volunteers (n = 59). Plasma levels of selected PUFAs along the LC-PUFA biosynthesis pathway were determined by transesterification and gas chromatography. CpG methylation levels for the main human LC-PUFA biosynthetic genes, fatty acid desaturases 1 (Fads1) and 2 (Fads2), and elongation of very long-chain fatty acids protein 5 (Elovl5), were assayed by bisulfite pyrosequencing. Associations between PUFA levels and diagnosis or suicide attempt status did not survive correction for multiple testing. However, MDD diagnosis and suicide attempts were significantly associated with DNA methylation in Elovl5 gene regulatory regions. Also the relative roles of PUFA levels and DNA methylation with respect to diagnostic and suicide attempt status were determined by least absolute shrinkage and selection operator logistic regression analyses. We found that PUFA associations with suicide attempt status were explained by effects of Elovl5 DNA methylation within the regulatory regions. The observed link between plasma PUFA levels, DNA methylation, and suicide risk may have implications for modulation of disease-associated epigenetic marks by nutritional intervention.
多不饱和脂肪酸（PUFA）状态与包括抑郁症和自杀风险在内的神经精神疾病有关。长链多不饱和脂肪酸（LC-PUFA）可从饮食中获取，或由较短链的前体脂肪酸亚油酸（LA，18:2n-6）和α-亚麻酸（ALA，18:3n-3）通过连续去饱和和延长反应生成。我们比较了有自杀未遂史（n = 22）和无自杀未遂史（n = 39）的重度抑郁症（MDD）患者以及年龄和性别匹配的健康志愿者（n = 59）中参与LC-PUFA生物合成的基因的DNA甲基化模式。通过酯交换和气相色谱法测定了LC-PUFA生物合成途径中选定PUFA的血浆水平。通过亚硫酸氢盐焦磷酸测序法检测了主要人类LC-PUFA生物合成基因脂肪酸去饱和酶1（Fads1）和2（Fads2）以及超长链脂肪酸延伸蛋白5（Elovl5）的CpG甲基化水平。PUFA水平与诊断或自杀未遂状态之间的关联在多重检验校正后不复存在。然而，MDD诊断和自杀未遂与Elovl5基因调控区域的DNA甲基化显著相关。此外，通过最小绝对收缩和选择算子逻辑回归分析确定了PUFA水平和DNA甲基化在诊断和自杀未遂状态方面的相对作用。我们发现，Elovl5基因调控区域内的DNA甲基化效应解释了PUFA与自杀未遂状态之间的关联。观察到的血浆PUFA水平、DNA甲基化与自杀风险之间的联系可能对通过营养干预调节疾病相关的表观遗传标记具有重要意义。
