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

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Macrophage Migration Inhibitory Factor (MIF) is a cytokine involved in neurogenesis and neuroprotection, primarily expressed in brain astrocytes.
• Serum MIF levels and genetic variations in the MIF gene promoter are associated with schizophrenia (SCZ).
• Hypoxia, a risk factor for SCZ, induces MIF expression via Hypoxia-Inducible Factor-1 (HIF-1) binding to the MIF promoter's Hypoxia Response Element (HRE).

Purpose of the Study:

• To investigate the association between a specific SNP in the MIF promoter's HRE and SCZ.
• To examine the effect of hypoxia on MIF expression in astrocytes and its regulation by the HIF pathway.

Main Methods:

• A case-control study genotyped SNP rs17004038 (C>A) in the MIF promoter's HRE in 1758 SCZ patients and 1507 controls.
• Primary mouse astrocyte cultures were exposed to hypoxia to assess MIF mRNA and protein expression, HIF-1 binding to the MIF promoter, and promoter activity.

Main Results:

• SNP rs17004038 was significantly associated with SCZ (p=0.0424, OR=1.445), identifying it as a genetic risk factor.
• Hypoxia increased MIF mRNA and protein levels, enhanced HIF-1 binding to the MIF promoter, and promoter activity was reduced by HRE mutations or deletion.
• These findings indicate that the HRE in the MIF promoter is crucial for hypoxia-induced MIF expression.

Conclusions:

• SNP rs17004038 in the MIF promoter's HRE is a significant genetic risk factor for SCZ.
• The study suggests that the pathophysiology of SCZ may involve the suppression of hypoxia and HIF pathway-induced MIF expression due to this genetic variation.