Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia

Abstract

Background Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. Methods We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. Results SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. Conclusion These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population

“…Genotyping was performed as previously described. 10 , 17 The MIF gene is located on chromosome 22q11.23 (GenBank accession No. NM_002415).…”

“…Therefore, we hypothesized that there are associations between suicide completion and the SNP rs17004038 in the HRE of the MIF promoter. Our previous study of MIF in patients with schizophrenia has failed to obtain information from each patient on suicidal risk, including suicidal ideation 17 . Docherty et al 21 .…”

“… 15 , 16 We previously reported that the SNP rs17004038 was associated with schizophrenia and disrupted hypoxia‐induced MIF expression via the HIF pathway in primary cultured astrocytes derived from the neonatal mouse forebrain. 17 We described the possibility that hypoxia increases the risk of schizophrenia by inhibiting MIF‐mediated hippocampal development. Perinatal hypoxia is a risk for schizophrenia.…”

“…Our previous study of MIF in patients with schizophrenia has failed to obtain information from each patient on suicidal risk, including suicidal ideation. 17 Docherty et al 21 conducted meta-analysis integrating GWAS for patients with suicidal behaviors, identifying 12 risk loci. However, most studies did not target suicide deaths.…”