Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke

Kim, Dong Hwan; Yoo, Seung Don; Chon, Jinmann; Yun, Dong Hwan; Kim, Hee Sang; Kim, Su Kang; Chung, Joo Ho; Kang, Jin Kyu; Lee, Seung Ah

doi:10.3346/jkms.2016.31.3.430

Cited by 6 publications

(5 citation statements)

References 36 publications

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“…Interleukin-6 (IL-6) as a cytokine plays an important role in the "response to injury" model of endothelial cells and atherosclerosis (26), and it is encoded and regulated by the IL-6 receptor (IL6R) gene, which is located in the chromosome 1q21. Some studies revealed that polymorphisms of IL-6R increased the risk of ischemic stroke in patients with metabolic syndrome and were associated with the neurologic status of ischemic stroke patients (27,28). However, we did not find the associations between the other 18 SNPs and outcomes in our linkage analysis.…”

Section: Discussioncontrasting

confidence: 80%

Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population

Chen,

Qing,

Luo

et al. 2024

Front. Neurol.

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AimTo identify the associations of 19 single nucleotide polymorphisms (SNPs) in genes involved in inflammation and endothelial function and carotid atherosclerosis with subsequent ischemic stroke and other vascular events in the high-risk stroke population.MethodsThis was a multicenter community-based sectional survey and prospective cohort study in Sichuan, southwestern China. Eight communities were randomly selected, and the residents in each community were surveyed using a structured face-to-face questionnaire. Carotid ultrasonography and DNA information were obtained from 2,377 out of 2,893 individuals belonging to a high-risk stroke population. Genotypes of the 19 SNPs in genes involved in inflammation and endothelial function were measured. All the 2,377 subjects were followed up for 4.7 years after the face-to-face survey. The primary outcome was ischemic stroke, and the secondary outcome was a composite of vascular events.ResultsAmong the 2,377 subjects, 2,205 (92.8%) completed a 4.7-year follow-up, 947 (42.9%) had carotid atherosclerosis [372 (16.9%) carotid vulnerable plaque, 405 (18.4%) mean IMT > 0.9 mm, 285 (12.0%) carotid stenosis ≥15%]. Outcomes occurred in 158 (7.2%) subjects [92 (4.2%) ischemic stroke, 17 (0.8%) hemorrhagic stroke, 48 (2.2%) myocardial infarction, and 26 (1.2%) death] during follow-up. There was a significant gene–gene interaction among ITGA2 rs1991013, IL1A rs1609682, and HABP2 rs7923349 in the 19 SNPs. The multivariate logistic regression model revealed that carotid atherosclerosis and the high-risk interactive genotypes among the three SNPs were independent with a higher risk for ischemic stroke (OR = 2.67, 95% CI: 1.52–6.78, p = 0.004; and OR = 3.11, 95% CI: 2.12–9.27, p < 0.001, respectively) and composite vascular events (OR = 3.04, 95% CI: 1.46–6.35, p < 0.001; and OR = 3.23, 95% CI: 1.97–8.52, p < 0.001, respectively).ConclusionThe prevalence of carotid atherosclerosis was shown to be very high in the high-risk stroke population. Specific SNPs, interactions among them, and carotid atherosclerosis were independently associated with a higher risk of ischemic stroke and other vascular events.

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Section: Discussioncontrasting

confidence: 80%

Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population

Chen,

Qing,

Luo

et al. 2024

Front. Neurol.

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“…The present study found that Klotho overexpression induced by LV-KL directly inhibited RIG-I expression in the ischemic brain. Additionally, a recent study showed that Klotho gene overexpression significantly decreased IL-6 production in HUVECs with or without inflammatory challenge ( Xia et al, 2016 ), and IL-6 receptor polymorphisms contributed to neurological status in ischemic stroke patients ( Kim et al, 2016 ). The binding of IL-6 to the IL-6 receptor activates intracellular signaling cascades and the production of C-reactive protein (CRP) and other cytokines ( Wang et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Klotho against Ischemic Brain Injury Is Associated with Inhibition of RIG-I/NF-κB Signaling

Zhou

Shi

et al. 2018

Front. Pharmacol.

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Aging is the greatest independent risk factor for the occurrence of stroke and poor outcomes, at least partially through progressive increases in oxidative stress and inflammation with advanced age. Klotho is an antiaging gene, the expression of which declines with age. Klotho may protect against neuronal oxidative damage that is induced by glutamate. The present study investigated the effects of Klotho overexpression and knockdown by an intracerebroventricular injection of a lentiviral vector that encoded murine Klotho (LV-KL) or rat Klotho short-hairpin RNA (LV-KL shRNA) on cerebral ischemia injury and the underlying anti-neuroinflammatory mechanism. The overexpression of Klotho induced by LV-KL significantly improved neurobehavioral deficits and increased the number of live neurons in the hippocampal CA1 and caudate putamen subregions 72 h after cerebral hypoperfusion that was induced by transient bilateral common carotid artery occlusion (2VO) in mice. The overexpression of Klotho significantly decreased the immunoreactivity of glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1, the expression of retinoic-acid-inducible gene-I, the nuclear translocation of nuclear factor-κB, and the production of proinflammatory cytokines (tumor necrosis factor α and interleukin-6) in 2VO mice. The knockdown of Klotho mediated by LV-KL shRNA in the brain exacerbated neurological dysfunction and cerebral infarct after 22 h of reperfusion following 2 h middle cerebral artery occlusion in rats. These findings suggest that Klotho itself or enhancers of Klotho may compensate for its aging-related decline, thus providing a promising therapeutic approach for acute ischemic stroke during advanced age.

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“…IL-6 has been detected in plasma and cerebrospinal fluid of stroke patients, and IL-6 immunoreactivity has been detected in microglia and cortical neurons of ischemic stroke models ( 96 ). In patients, IL-6R polymorphisms are also related to poor neurological outcomes ( 97 ), although IL-6 polymorphisms did not show an increased risk of ischemic stroke ( 98 ). To add to the conflicting observations, IL-6-deficient mice and mice treated with an IL-6 receptor antagonist mice did not have improved outcomes compared to untreated mice ( 99 , 100 ).…”

Section: Inflammation In Strokementioning

confidence: 99%

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

2017

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While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.

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Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke

Cited by 6 publications

References 36 publications

Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population

Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population

Protective Effect of Klotho against Ischemic Brain Injury Is Associated with Inhibition of RIG-I/NF-κB Signaling

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

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