13 research outputs found
Identification of Epigenetic Signature Associated With Alpha Thalassemia/Mental Retardation X-linked Syndrome
BACKGROUND: Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene
RESULTS: We performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation epi-signature in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.
CONCLUSION: Most significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients wit
Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium: a study protocol.
INTRODUCTION:
Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated.
METHODS AND ANALYSIS:
To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease.
ETHICS AND DISSEMINATION:
BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders
Coma in adult cerebral venous thrombosis:The BEAST study
Background and purpose: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. Methods: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. Results: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5–60) versus 40 (33–47) years in the coma (p = 0.04) and 44.5 (34–58) versus 37 (29–48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age-and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0–3.4, p = 0.04 to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52–0.68, p = 0.01). Conclusions: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women
Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis
Objective Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. Methods A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. Results In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 x 10(-24); odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 x 10(-16)). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 x 10(-16)) increased risk of CVT compared with individuals with blood group O. Interpretation We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021Peer reviewe
Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium : a study protocol
Introduction: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated. Methods and analysis: To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease. Ethics and dissemination: BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.Peer reviewe
Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome
Identification of alcA, a Bordetella bronchiseptica gene necessary for alcaligin production
MOESM1 of Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome
Additional file 1: Figure S1. Methylation string diagrams of significantly altered regions in ATR-X patients and controls. Bisulfite mutagenesis and sequencing analysis was performed in approximately 20 alleles from each sample, and individual alleles are represented as a string of CpGs. The total average methylation for each sample is indicated. Unmethylated CpGs are represented as empty circles, and methylated CpGs as filled circles
MOESM2 of Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome
Additional file 2: Table S1. ATR-X methylation; significant regions detected by methylation array in ATR-X patients (n = 17) compared with controls (n = 210) using cutoff of probes >3, estimate >15%, F value >50, p value <0.01
Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium: a study protocol
Introduction: Cerebral venous thrombosis (CVT) is a rare cerebrovascular
condition accounting for < 1% of all stroke cases and mainly affects
young adults. Its genetic aetiology is not clearly elucidated.
Methods and analysis: To better understand the genetic basis of CVT, we
have established an international biobank of CVT cases, Biorepository to
Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to
recruit highly phenotyped cases initially of European descent and later
from other populations. To date we have recruited 745 CVT cases from 12
research centres. As an initial step, the consortium plans to undertake
a genome-wide association analysis of CVT using the Illumina Infinium
HumanCoreExome BeadChip to assess the association and impact of common
and low-frequency genetic variants on CVT risk by using a case-control
study design. Replication will be performed to confirm putative
findings. Furthermore, we aim to identify interactions of genetic
variants with several environmental and comorbidity factors which will
likely contribute to improve the understanding of the biological
mechanisms underlying this complex disease.
Ethics and dissemination: BEAST meets all ethical standards set by local
institutional review boards for each of the participating sites. The
research outcomes will be published in international peer-reviewed
open-access journals with high impact and visibility. The results will
be presented at national and international meetings to highlight the
contributions into improving the understanding of the mechanisms
underlying this uncommon but important disease. This international DNA
repository will become an important resource for investigators in the
field of haematological and vascular disorders