Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia
Bibliographic record
Abstract
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium. METHODS: We genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering. RESULTS: None of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13-6.80, p = .026). CONCLUSION: We did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".