Dataset Information

Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation.

ABSTRACT:

Background

Polymorphisms in the proinflammatory cytokine interleukin (IL)-1beta gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1beta and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients.

Method

Two IL-1beta promoter SNPs (-511C-->T, -31T-->C) and 1 synonymous coding SNP in exon 5 at +3953C-->T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation.

Results

Subjects with the -31 CC genotype (HR = 2.7; 95% CI 1.1-6.6; p = 0.029) or the -511 TT genotype (HR = 2.6; 95% CI 1.1-6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The +3953C-->T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1beta promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001).

Conclusion

IL-1beta promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1beta cytokine, may play an important role in ICH.

SUBMITTER: Kim H

PROVIDER: S-EPMC2649796 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Publications

Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation.

Kim Helen H Hysi Pirro G PG Pawlikowska Ludmila L Poon Annie A Burchard Esteban González EG Zaroff Jonathan G JG Sidney Stephen S Ko Nerissa U NU Achrol Achal S AS Lawton Michael T MT McCulloch Charles E CE Kwok Pui-Yan PY Young William L WL

Cerebrovascular diseases (Basel, Switzerland) 20081218 2

<h4>Background</h4>Polymorphisms in the proinflammatory cytokine interleukin (IL)-1beta gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1beta and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients.<h4>Method</h4>Two IL-1beta promoter SNPs (-511C-->T, -31T-->C) and 1 synonymous coding SNP in exon 5 at +3953C- ...[more]

PMID: 19092239

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Project description:ImportanceIntracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) ε4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE ε4 carriers that may increase the risk of ICH.ObjectiveTo assess whether APOE ε4 is associated with a higher risk of ICH in patients with a known AVM.Design, setting, and participantsThis cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the ε status.Main outcomes and measuresFor each study, the association between APOE ε4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression.ResultsThe discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE ε4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE ε4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03).Conclusions and relevanceThe results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE ε4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.

Project description:Children with untreated brain arteriovenous malformations (bAVM) are at risk of encountering life-threatening hemorrhage very early in their lives. The primary aim of invasive treatment is to reduce unfavorable outcome associated with a bAVM rupture. A better understanding of the morbidity of bAVM hemorrhage might be helpful for weighing the risks of untreated bAVM and invasive treatment. Our aim was to assess the clinical outcome after bAVM rupture and identify features to predict severe hemorrhage in children.We identified all consecutive children admitted to our institution for bAVMs between July 2009 and December 2014. Clinical outcome after hemorrhagic presentation and subsequent hemorrhage was evaluated using the modified Rankin Scale (mRS) for children. The association of demographic characteristics and bAVM morphology with severe hemorrhage (mRS >3 or requiring emergency hematoma evacuation) was studied using univariate and multivariable regression analyses. A nomogram based on multivariable analysis was formulated to predict severe hemorrhage risk for individual patients.A total of 134 patients were identified with a mean treatment-free follow-up period of 2.1 years. bAVM ruptured in 83 (62%) children: 82 had a hemorrhage at presentation and 6 of them experienced a recurrent hemorrhage during follow-up; 1 patient had other diagnostic symptoms but bled during follow-up. Among them, 49% (41/83) had a severe hemorrhage; emergency hematoma evacuation was required in 28% of them (23/83), and 24% (20/83) remained as disabled (mRS ?3) at last follow-up. Forty-six percent (38/82) of children with hemorrhagic presentation were severely disabled (mRS >3). Forty-three percent (3/7) were severely disabled after subsequent hemorrhage. The annual rate of severe subsequent hemorrhage was 1% in the overall cohort and 3.3% in children with ruptured presentation. All the subsequent severe hemorrhage events occurred in children with severe hemorrhage history (7%, 3/41). Periventricular location, non-temporal lobe location, and long draining vein were predictors for severe hemorrhage in pediatric untreated bAVMs. A nomogram based on bAVM morphology was contracted to predict severe hemorrhage risk for individual patients, which was well calibrated and had a good discriminative ability (adjusted C-statistic, 0.72).Evaluating bAVM morbidity and morphology might be helpful for weighing the risks of untreated bAVM in pediatric patients.

Project description:The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. This retrospective study included 262 adult patients with unruptured bAVMs who underwent upfront SRS. Hemorrhagic events were defined as evidence of blood on CT or MRI. The morphology of bAVMs was evaluated using automated segmentation which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as the ratio of vessel to brain tissue, categorized bAVMs into compact and diffuse types based on the optimal cutoff. Cox proportional hazard model was used to identify the independent factors for post-SRS hemorrhage. The median clinical follow-ups was 62.1 months. Post-SRS hemorrhage occurred in 13 (5.0%) patients and one of them had two bleeds, resulting in an annual bleeding rate of 0.8%. Multivariable analysis revealed bAVM morphology (compact versus diffuse), bAVM volume, and prescribed margin dose were significant predictors. The post-SRS hemorrhage rate increased with larger bAVM volume only among the diffuse nidi (1.7 versus 14.9 versus 30.6 hemorrhage per 1000 person-years in bAVM volume < 20 cm3 versus 20-40 cm3 versus > 40 cm3; p = 0.022). The significantly higher post-SRS hemorrhage rate of Spetzler-Martin grade IV-V compared with grade I-III bAVMs (20.0 versus 3.3 hemorrhages per 1000 person-years; p = 0.001) mainly originated from the diffuse bAVMs rather than the compact subgroup (30.9 versus 4.8 hemorrhages per 1000 person-years; p = 0.035). Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (> 40 cm3) bAVMs and the diffuse Spetzler-Martin IV-V bAVMs. These findings may help guide patient selection of SRS for the unruptured bAVMs.

Project description:Objectives: Rupture of a brain arteriovenous malformation (bAVM) can cause intracranial hemorrhage and severe clinical outcomes. At present, the mechanisms of bAVM-related hemorrhage are poorly understood. This study aimed to summarize the potential genetic risk factors for bAVM-related hemorrhage and appraise the methodological quality of existing genetic studies on bAVM-related hemorrhage using a cross-sectional design. Methods: A systematic literature search was conducted on genetic studies associated with bAVM-related hemorrhage published in PubMed, Embase, Web of Science, China National Knowledge Internet, and Wangfang databases, up to November 2022. Subsequently, a cross-sectional study was performed to describe the potential candidate genetic variants of bAVM associated with risk of hemorrhage and to evaluate the methodological quality of the identified studies using the Newcastle-Ottawa quality assessment scale and Q-genie tool. Results: Of the 1811 records identified in the initial search, nine studies met the filtering criteria and were included. Twelve single nucleotide polymorphisms (SNPs), including IL6 rs1800795, IL17A rs2275913, MMP9 rs9509, VEGFA rs1547651, and EPHB4 rs314353, rs314308, and rs314313, were associated with bAVM-related hemorrhage. However, only 12.5% of the evaluated SNPs showed statistical power> 0.80 (α = 0.05). Methodological quality assessment revealed significant flaws in the designs of the included studies, such as less reliable representativeness of recruited individuals, short follow-up periods in cohort studies, and less comparability between groups of hemorrhagic and non-hemorrhagic patients. Conclusion: IL1B, IL6, IL17A, APOE, MMP9, VEGFA and EPHB4 were potentially associated with bAVM-related hemorrhage. The methodological designs of the analyzed studies required improvement in order to obtain more reliable results. Regional alliances and rare disease banks need to be established to recruit large numbers of bAVM patients (especially familial and extreme-trait cases) in a multicenter, prospective cohort study with an adequate follow-up period. Furthermore, it is important to use advanced sequencing techniques and efficient measures to filter candidate genetic variants.

Dataset Information

Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation.

Background

Method

Results

Conclusion

Publications

Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation.

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