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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.

SUBMITTER: Gu XX

PROVIDER: S-EPMC8064973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The microRNA-17-92 (miR-17-92) cluster is one of the most extensively studied miRNA clusters. Abnormal expression of the cluster has been found to play important role in different kinds of human diseases, including ischemic stroke (IS). The aim of our study was to investigate the association between three polymorphisms (rs1491034, rs9301654 and rs982873) in the promoter of the miR-17-92 cluster and risk of IS. METHODS:Three hundred and ninety-eight patients with IS and 397 control subjects were included. The genotypes of the three polymorphisms were determined by Snapshot SNP genotyping assay. Relative expression of the cluster in peripheral blood mononuclear cells (PBMCs) of cases and controls were examined by quantitative real-time PCR. RESULTS:Significant association between rs9301654 polymorphism and risk of IS were observed basing on genotype, model and allele analyses (GA vs. AA: adjusted OR?=?0.63, 95% CI: 0.41~0.97, P?=?0.037; GG vs. AA: adjusted OR?=?0.23, 95% CI: 0.07~0.78, P?=?0.018; GA?+?GG vs. AA: adjusted OR?=?0.57, 95% CI: 0.38~0.87, P?=?0.009; GA?+?AA vs. GG: adjusted OR?=?0.27, 95% CI: 0.08~0.89, P?=?0.032; G vs. A: adjusted OR?=?0.58, 95% CI: 0.40~0.83). Haplotype analysis showed that TGC and TGT haplotypes were associated with decreased risk of IS (OR?=?0.59, 95% CI: 0.40~0.87, P?=?0.007 for TGC haplotype; OR?=?0.21, 95% CI: 0.06~0.75, P?=?0.009 for TGT haplotype). Importantly, we found the expression of miR-17-5p was significant higher while miR-19a-3p was significant lower in patient with IS compared with the control group (P?<?0.01), and patients with rs9301654GG or GA genotype displayed lower level of miR-19a-3p compared with the AA genotype (P?<?0.01). CONCLUSIONS:Our findings indicated that rs9301654 polymorphism in the promoter of miR-17-92 cluster may be associated with susceptibility of IS in the Chinese population. However, we found that rs9301654 polymorphism and its respective gene expression did not demonstrate consistent association with IS in the Chinese population. Further studies such as gene-gene interaction are warranted to reveal the role of miR-19a and its regulatory genes in the etiology of IS.

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

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