Interstitial lung disease in STING-associated vasculopathy with onset in infancy (SAVI): preliminary genotype-phenotype correlation
Bibliographic record
Abstract
Some monogenic interferonopathies are caused by innate immune dysregulation and form a subclass of autoinflammatory disorders characterized by systemic inflammation due to chronic Type I interferon stimulation. STING-Associated Vasculopathy with Onset in Infancy (SAVI) is an IFN-mediated disease caused by gain-of-function mutations in TMEM173 , the gene encoding the stimulator of interferon genes (STING). This study was undertaken to understand the variable disease severity of the interstitial lung disease (ILD) in SAVI patients. We hypothesized that the severity of the interstitial lung disease may be modulated by a common SNP (R232H, rs1131769) that is functionally associated with decreased IFNB1 transcription. We studied nine SAVI patients with N154S, V155M, or V147L mutations. Lung involvement was assessed by chest computed tomography (CT) and pulmonary function tests (PFTs) for all patients, a lung biopsy was available for five patients. Peripheral blood genomic DNA samples were obtained and TMEM173 (NM_198282.3) was sequenced by Sanger technique. STING function was evaluated in the different TMEM173 haplotypes by IFNB1 Luciferase Reporter assays performed with cells transfected with wildtype or mutant TMEM173 on the R232 and the H232 backgrounds. We described the clinical features of ILD in nine SAVI patients. Six patients had evidence of severe ILD characterized by moderate to severe abnormalities on chest CT, PFTs and/or lung biopsy. Two patients presented with mild ILD and one did not have any evidence of ILD. Four out of the six patients with severe ILD succumbed to pulmonary complications. Five patients with severe ILD were homozygous for R232 (R232/R232) and one was heterozygous for the SNP. Conversely, the two patients with mild ILD were heterozygous (R232/H232) and the patient without ILD was homozygous for the H232 allele (H232/H232). Thus, the severity of interstitial lung disease seems to correlate with the STING haplotype. Transfection of HEK293T cells with the H232 TMEM173 haplotype with or without SAVI causing mutations results in decreased IFNB1 expression in the presence of both low affinity and high affinity STING stimulator cGAMP in comparison with cells transfected with the R232 haplotype. These findings suggest that the H232 haplotype background may be protective from the development of ILD. The variable presentation and severity of ILD in SAVI patients seems to correlate with the TMEM173 haplotype at position 232 and possibly with the local induction of an IFN response. Our data suggest that common variants can modify disease expression specific to one organ and provide a model to assess the variable disease phenotype in other interferonopathies.
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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) | 0.000 | 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".