Hyaluronidase synthase 3 (<i>HAS3</i>) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group.
Bibliographic record
Abstract
10004 Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".