Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia
Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia
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DOI：
10.1016/j.pnpbp.2018.01.001
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发表时间：
2018-04
影响因子：
5.6
通讯作者：
S. Okazaki;A. Hishimoto;Ikuo Otsuka;Yuichiro Watanabe;Shusuke Numata;S. Boku;Naofumi Shimmyo;M. Kinoshita
中科院分区：
文献类型：
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作者：
S. Okazaki;A. Hishimoto;Ikuo Otsuka;Yuichiro Watanabe;Shusuke Numata;S. Boku;Naofumi Shimmyo;M. Kinoshita
大量研究表明，免疫系统失衡在精神分裂症中起着重要作用。巨噬细胞迁移抑制因子（MIF）是一种多效性细胞因子。它在各种生物过程中起着多种作用，包括炎症和神经发生。此外，几项详尽的血清蛋白质组学分析研究已经确定MIF是精神分裂症的潜在生物标志物。在这里，我们研究了精神分裂症患者和对照组的血清和死后前额叶皮层中的MIF蛋白水平。此外，我们还研究了theMIFgene启动子区域的两个功能多态性（mif - 794catt5 - 8微卫星和mif - 173g / c单核苷酸多态性[SNP]）与精神分裂症的关系。方法采用酶联免疫吸附试验（ELISA）测定血清MIF水平（51例患者对照86例对照组），采用western blotting测定死后脑MIF水平（18例患者对照22例对照组）。随后，我们用荧光片段法对themif - 794catt5 - 8微卫星进行基因分型，用TaqMan SNP基因分型对theMIF-173G/CSNP进行基因分型（1483例患者对1454例对照组）。结果精神分裂症患者血清MIF水平显著高于对照组（p= 0.00118），且与抗精神病药剂量呈正相关（Spearman’s sr= 0.222,p= 0.0402）。此外，血清MIF水平高（≥40 ng/mL）的患者发病年龄比血清MIF水平低（< 40 ng/mL）的患者早（p= 0.0392）。然而，死后脑MIF水平在精神分裂症患者和对照组之间没有差异。关联研究显示，att6 - ghaplotype在名义上与精神分裂症显著相关（p= 0.0338），而att6等位基因和catt6 - ghaplotype与女性青少年发作性精神分裂症（AsOS）显著相关（校正后的dp= 0.0222和p= 0.0147）。结论血清MIF水平是精神分裂症的潜在药效学和/或监测指标，并与多巴胺拮抗剂以外的新型抗精神病作用有关。此外，theMIFgene多态性与精神分裂症的风险相关，特别是在青少年女性中，并且是精神分裂症的潜在分层标记。对MIF的进一步研究有助于阐明精神分裂症的病理生理学和抗精神病药物的作用。
BackgroundNumerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in theMIFgene promoter region (MIF-794CATT5–8microsatellite andMIF-173G/Csingle-nucleotide polymorphism [SNP]) with schizophrenia.MethodsWe measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped theMIF-794CATT5–8microsatellite with a fluorescence-based fragment assay and theMIF-173G/CSNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls).ResultsSerum MIF levels were significantly higher in patients with schizophrenia than in controls (p= 0.00118), and were positively correlated with antipsychotic dose (Spearman'sr= 0.222,p= 0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥ 40 ng/mL) than those with a low serum MIF level (< 40 ng/mL) (p= 0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that theCATT6-Ghaplotype was nominally significantly associated with schizophrenia (p= 0.0338), and that theCATT6allele andCATT6-Ghaplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (correctedp= 0.0222 andp= 0.0147, respectively).ConclusionsThese results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, theMIFgene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.