72 research outputs found
Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes
BACKGROUND: There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-beta signalling pathways, and the disease phenotype appears to be unmasked or provoked by angiogenesis in man and animal models. In a previous study, we mapped a new locus for HHT (HHT3) to a 5.7 Mb region of chromosome 5. Some of the polymorphic markers used had been uninformative in key recombinant individuals, leaving two potentially excludable regions, one of which contained loci for attractive candidate genes encoding VE Cadherin-2, Sprouty4 and FGF1, proteins involved in angiogenesis. METHODS: Extended analyses in the interval-defining pedigree were performed using informative genomic sequence variants identified during candidate gene sequencing. These variants were amplified by polymerase chain reaction; sequenced on an ABI 3730xl, and analysed using FinchTV V1.4.0 software. RESULTS: Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints. These reduced the uninformative centromeric region from 141.2-144 Mb to between 141.9-142.6 Mb, and the uninformative telomeric region from 145.2-146.9 Mb to between 146.1-146.4 Mb. CONCLUSIONS: The HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original HHT3 interval. Strong candidates VE-cadherin-2 and Sprouty4 cannot be HHT3
Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.
Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses
Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.
<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div
Endothelial Cell Processing and Alternatively Spliced Transcripts of Factor VIII: Potential Implications for Coagulation Cascades and Pulmonary Hypertension
Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. Methodology/Principal Findings: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by rt-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab–reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 59 exons within the int22h-1 repeat responsible for intron 2
7-day weighed food diaries suggest patients with hereditary hemorrhagic telangiectasia may spontaneously modify their diet to avoid nosebleed precipitants
Hereditary hemorrhagic telangiectasia (HHT) poses substantial burdens due to nosebleeds and iron deficiency resulting from recurrent hemorrhagic iron losses. Recent studies by our group found surprising links between HHT nosebleeds and certain food groups. In this letter, we report 7-day weighed food diary assessments of an unselected group of 25 UK patients with HHT whose nosebleeds ranged from mild to severe (median epistaxis severity score 4.66, range 0.89– 9.11). The diaries provide evidence that food items most commonly reported to provoke nosebleeds were ingested by fewer HHT patients, compared to food items less commonly reported to provoke nosebleeds (chi-squared p <0.001)
Functional filter for whole genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5kb from coding DN
Acknowledgments: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The work was cofounded by the National Institute for Health Research Imperial Biomedical Research Centre, the D’Almeida Charitable Trust, and Imperial College Healthcare NHS Trust. AA was supported by Prince Sultan Military Medical City, Saudi Arabia. MAA was supported by the National Institutes of Health (grant R35HL140019). The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank the National Health Service staff of the UK Genomic Medicine Centres and the participants for their willing participation; the Genomics England Clinical Research Interface team, specifically Susan Walker, for separately reviewing bam file variant sequences; Charlotte Bevan, Michael Hubank and Santiago Vernia for helpful discussions and manuscript review; and our academic and public partners within the NIHR Imperial BRC’s Social Genetic and Environmental Determinants of Health (SGE) theme. We specifically thank the presented families for confirmation of their clinical phenotypes and consent to share in this manuscript. The views expressed are those of the authors and not necessarily those of funders, the NHS, the NIHR, or the Department of Health and Social Care.Peer reviewedPublisher PD
Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency
BACKGROUND: Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). METHODOLOGY/PRINCIPAL FINDINGS: The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin(2) explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. CONCLUSIONS/SIGNIFICANCE: HAIR values, providing an indication of individuals' iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses
Specifications of the ACMG/AMP variant curation guidelines for hereditary hemorrhagic telangiectasia genes - ENG and ACVRL1
13 p.-1 fig.-3 tab.The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution. © 2024 Desiree DeMille et al.The authors would like to acknowledge the support of the ClinGen Sequence Variant Interpretation Working Group and the Hemostasis/Thrombosis Clinical Domain Working Group, especially Kristy Lee. The authors would also like to acknowledge the participation of previous ClinGen HHT VCEP members: Pernille Tørring, Hans Kristian Ploos van Amstel, and Helen Arthur. CLS acknowledges support from the NIHR Imperial Biomedical Research Centre. LJ acknowledges support from Knut and Alice Wallenberg Foundation grant (2018.0042) and Swedish Research Council grant (2020-04936). CB was supported by Consejo Superior de Investigaciones Cientificas (CSIC) of Spain. CC, CO,and AS are funded by the Italian Ministry of University and
Research, “Fondo Beneficenza Intesa Sanpaolo,” and Banca d’Italia. ClinGen is primarily funded by the National Human Genome Research Institute (NHGRI) with cofunding from the National Cancer Institute (NCI), through the following grants: Baylor/Stanford (U24HG009649), Broad/Geisinger(U24HG006834), and UNC/Kaiser (U24HG009650).Peer reviewe
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