A Functional Polymorphism in HIF-3α Is Related to an Increased Risk of Ischemic Stroke

Abstract

Hypoxia-inducible factor-3α (HIF-3α), a member of HIF family, can mediate adaptive responses to low oxygen and ischemia. It is believed that HIF plays crucial roles in stroke-related diseases. However, there are no reports on the association between HIF-3α genetic variants and ischemic stroke (IS) susceptibility. Therefore, we examined the association between HIF-3α gene polymorphisms (rs3826795, rs2235095, and rs3764609) and IS risk. The study population included 302 controls and 310 patients with ischemic stroke. Three polymorphisms in HIF-3α (rs3826795, rs2235095, and rs3764609) were genotyped using SNPscan technique. Our study showed a strong association of rs3826795 in HIF-3α with the risk of IS. The genotype and allele frequencies were shown to differ between the two groups. The rs3826795 in an intron of HIF-3α was related to a prominent increased IS risk (AA vs GG adjusted odd ratio [OR], 2.21; 95% confidence intervals [95% CI], 1.10–4.44; P = 0.03; AA vs AG/GG OR = 1.74, 95% CI, 1.02–2.97, P = 0.04; A vs G OR = 1.48, 95% CI, 1.05–2.07, P = 0.02). Logistic regression analysis suggested that rs3826795 posed a risk factor for IS in addition to common factors. Furthermore, when compared to controls, increased levels of homocysteic acid and level of non-esterified fatty acid were found in the cases (P < 0.01). However, no significant association was found between rs2235095 or rs3264609 and IS risk. These findings indicated that the rs3826795 polymorphism may be a potential target for predicting the risk of IS.

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

“…63 Relatively little is known of the function of HIF-3. It is considered to be a negative regulator of HIF-1 and HIF-2 by competition for HIF-1β 60,65 and plays a role in stroke-related diseases. 60 HIF-1 and HIF-2 are closely related but transcription of genes differs and HIF-2 is stable at higher oxygen concentrations than HIF-1.…”

“…It is considered to be a negative regulator of HIF-1 and HIF-2 by competition for HIF-1β 60,65 and plays a role in stroke-related diseases. 60 HIF-1 and HIF-2 are closely related but transcription of genes differs and HIF-2 is stable at higher oxygen concentrations than HIF-1. 61 HIF-1 is more acutely responsive to hypoxia, whereas HIF-2 is more chronically responsive.…”

“…HIF-1, HIF-2, and HIF-3 are heterodimeric transcription factors consisting of an oxygen-labile HIF-1α, HIF-2α, or HIF-3α monomer and a common stable β monomer. 60,61 The labile monomers are continuously expressed and in normoxic conditions rapidly oxygendependently hydroxylated, ubiquitinated, and proteosomally degraded. They become stabilized in hypoxic conditions.…”

Role of hypoxia-inducible factor in postoperative delirium of aged patients: A review

“…[4][5][6] Hypoxia stimulates the expression of hypoxia-inducible factor-1 (HIF-1), which controls the hypoxic response. [10][11][12][13][14][15] HIF-1 may have a protective role in regulating neuron apoptosis in neonatal hypoxia-ischemia brain damage and may promote the repair and rebuilding process in the brain that was damaged by hypoxia and ischemia. [10] Animal experiments show that neuron-specific loss of HIF-1 increases ischemic brain injury, and the recovery of neural function in ischemic rats is related to the increased expression of hypoxia-inducible factor subtype 1α (HIF-1α).…”

“…[10] Animal experiments show that neuron-specific loss of HIF-1 increases ischemic brain injury, and the recovery of neural function in ischemic rats is related to the increased expression of hypoxia-inducible factor subtype 1α (HIF-1α). [10,11] And more recently, anesthetics and perioperative drugs have been reported to affect HIF-1 activity. [16][17][18][19][20] Research reports that the anesthetics inhibit HIF-1 activation and downstream gene expression.…”