A role of TNF‐<i>α</i> gene variant on juvenile ischemic stroke: a case–control study

Rubattu, Speranza; Speranza, Rino; Ferrari, Marco; Evangelista, Anna; Beccia, Mario; Stanzione, Rosita; Assenza, Gabriele Egidy; Volpe, Massimo; Rasura, Maurizia

doi:10.1111/j.1468-1331.2005.01136.x

Cited by 53 publications

(39 citation statements)

References 26 publications

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“…The relevance of these experimental findings was extended to a human cohort of early‐onset ischemic stroke cases. This population was previously investigated for polymorphisms of candidate genes encoding procoagulant and inflammatory factors and methionine metabolism components: for a polymorphism of type C natriuretic peptide receptor (NPR3) promoter gene and for polymorphisms of chromosome 12p13 25, 26, 27, 28. In this population, an SNP study revealed a significant association between an intronic marker (rs11237379) of NDUFC2 and early‐onset ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Rubattu

Castro

Schulz

et al. 2016

JAHA

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BackgroundThe genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance.Methods and ResultsNine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006).ConclusionsA significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.

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Section: Discussionmentioning

confidence: 99%

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Rubattu

Castro

Schulz

et al. 2016

JAHA

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“…Several studies have documented a TNF(Ϫ308) allelic association with ischemic stroke, but the results have not been consistent across populations. Whereas the TNF(Ϫ308)A allele was found to be protective in Korean adults with ischemic stroke 15 and patients with lacunar infarcts, 16 it conferred an increased risk of ischemic stroke in younger Italian patients 17 and patients with a preceding febrile episode. 18 Another study in Turkish children found no association between the TNF(Ϫ308) SNP and stroke.…”

Section: Discussionmentioning

confidence: 99%

Confirmation of an Association Between the TNF(−308) Promoter Polymorphism and Stroke Risk in Children With Sickle Cell Anemia

Hoppe

Klitz

D’Harlingue

et al. 2007

Stroke

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Background and Purpose-The etiology of stroke in children with sickle cell anemia (SCA) is complex and poorly understood. Growing evidence suggests that genetic factors beyond the sickle cell mutation influence stroke risk in SCA. We previously reported risk associations with polymorphisms in several proinflammatory genes in SCA children with ischemic stroke. The aim of this replication study was to confirm our previous findings of associations between the TNF(Ϫ308) G/A, IL4R 503 S/P, and ADRB2 27 Q/E polymorphisms and large vessel stroke risk. Methods-Using previously collected MRA data, we assessed an independent population of SCA children from the multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) for the presence or absence of large vessel stenosis. Samples were genotyped for 104 polymorphisms among 65 candidate vascular disease genes. Genotypic associations with risk of large vessel stroke were screened using univariable analysis and compared with results from our original study. Joint analysis of the 2 study populations combined was performed using multivariable logistic regression. Results-A total of 96 children (49 MRA-positive, 47 MRA-negative) were included in this study. Of the SNP associations previously identified in the original study, the TNF(Ϫ308) G/A association with large vessel stroke remained significant and the IL4R 503 S/P variant approached significance in the joint analysis of the combined study populations. Consistent with our original findings, the TNF(Ϫ308) GG genotype was associated with a Ͼ3-fold increased risk of large vessel disease (ORϭ3.27; 95% CIϭ1.6, 6.9; Pϭ0.006). Unadjusted analyses also revealed a previously unidentified association between the LTC4S(Ϫ444) A/C variant and large vessel stroke risk. Conclusions-Similar findings in 2 independent study populations strongly suggest that the TNF(Ϫ308) G/A promoter polymorphism is a clinically important risk factor for large vessel stroke in children with SCA. The previously observed association with the IL4R 503 S/P variant and the novel association with the LTC4S(Ϫ444) A/C variant suggest that these loci may also contribute to large vessel stroke risk in children with SCA.

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“…The inflammatory response associated with the ischemic injury can be influenced by functional polymorphisms in components of the immune system and consequently the final cerebral ischemic burden [2,3,4]. Recent reports suggested that promoter region polymorphism in the tumor necrosis factor-α (TNF-α) gene at position –308 is an important risk factor for large-vessel stroke in children with SCA [5,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Absence of Association between TNF-α Polymorphism and Cerebral Large-Vessel Abnormalities in Adults with Sickle Cell Anemia

et al. 2010

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Stroke is a serious complication of sickle cell anemia (SCA) affecting children and adults. Recent reports suggested that tumor necrosis factor-α (TNF-α) (–308) polymorphism is an important risk factor for stroke in children with SCA. The role of TNF-α polymorphism in the frequency of brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) abnormalities in adults with SCA is still uncertain. Our objective was to evaluate the frequency of TNF-α polymorphism in adults with SCA and to correlate it to brain MRI and MRA findings. TNF-α (–308) polymorphism was determined in 49 adults with SCA. All subjects were evaluated with brain MRI/MRA to establish the presence of intracranial abnormalities. Thirty-three (67.3%) had abnormal brain MRA scans, 8 (16.3%) had intracranial stenosis and 29 (59.2%) showed arterial tortuosity. Forty-one (83.7%) had the GG genotype and 8 had the GA genotype. There was no correlation between homozygosity for G allele and MRA or MRI abnormalities. Although TNF-α (–308) polymorphism is a potential predictor of the genetic risk for stroke in children, we found no association between the polymorphism and large vessel abnormalities in adults with SCA.

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A role of TNF‐α gene variant on juvenile ischemic stroke: a case–control study

Cited by 53 publications

References 26 publications

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Confirmation of an Association Between the TNF(−308) Promoter Polymorphism and Stroke Risk in Children With Sickle Cell Anemia

Absence of Association between TNF-α Polymorphism and Cerebral Large-Vessel Abnormalities in Adults with Sickle Cell Anemia

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