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Functional Genetic Variation in the 3'-UTRNTRK2 is Associated with Risk of Ischemic Stroke.

ABSTRACT: Background:Stroke is a leading cause of death and disability worldwide. It remains difficult to treat brain injury and improve functional rehabilitation after cerebral ischemia. Brain-derived neurotrophic factor (BDNF) is involved in ischemic stroke (IS) through interactions in the CREB1-BDNF-NTRk2 pathway. In this study, we aimed to determine the association of NTRK2 gene polymorphisms and the effects of intergenetic interactions in the Chinese population. Materials and Methods:A total of 400 patients diagnosed with IS and 400 healthy controls were enrolled for genotyping. Detailed sequence-based analysis was predicted through bioinformatical investigation. Polymorphisms associated with miRNA were analyzed by a dual-luciferase reporter assay system. Results:Analysis of clinical characteristics revealed that IS was highly associated with exposure to cigarette smoking, alcohol intake, as well as metabolic diseases, such as diabetes, hypertension, and higher serum triglyceride concentration. Three polymorphisms in NTRK2 located in the 3'-untranslated region (3'-UTR) were genotyped. Logistic regression analysis showed that IS patients with rs11140793, rs7047042, and rs1221 polymorphisms had a higher risk of stroke and indicated a worse short-term recovery. The mRNA level of NTRK2 was suppressed in a mutant genotype compared with wild genotype. The suppression of NTRK2 was induced by the gain-of-binding ability of certain miRNAs through the direct binding of 3'-UTR. Conclusion:Our research indicated that, by influencing the expression of NTRK2, the SNPs rs11140793, rs7047042, and rs1221 in the 3'UTR of NTRK2 can be used as risk factors for IS patients.

SUBMITTER: Shi J

PROVIDER: S-EPMC7669521 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Functional Genetic Variation in the 3'-UTRNTRK2 is Associated with Risk of Ischemic Stroke.

Shi Jiajia J Sun Ying Y Hua Jiajia J

Pharmacogenomics and personalized medicine 20201112

<h4>Background</h4>Stroke is a leading cause of death and disability worldwide. It remains difficult to treat brain injury and improve functional rehabilitation after cerebral ischemia. Brain-derived neurotrophic factor (<i>BDNF</i>) is involved in ischemic stroke (IS) through interactions in the <i>CREB1-BDNF-NTRk2</i> pathway. In this study, we aimed to determine the association of <i>NTRK2</i> gene polymorphisms and the effects of intergenetic interactions in the Chinese population.<h4>Materi ...[more]

PMID: 33209049

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Project description:Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ?3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Dataset Information

Functional Genetic Variation in the 3'-UTRNTRK2 is Associated with Risk of Ischemic Stroke.

Publications

Functional Genetic Variation in the 3'-UTRNTRK2 is Associated with Risk of Ischemic Stroke.

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