Evidence of somatic mitochondrial DNA mutations in primary open angle glaucoma: ARVO Annual Meeting Abstract
Bibliographic record
Abstract
The aim of this study was to determine the role of mitochondrial DNA (mtDNA) mutations in primary open angle glaucoma (POAG) using massively parallel sequencing. POAG patients and disease-negative controls were recruited and underwent ophthalmic assessment and DNA extraction from blood leucocytes. In a subset of this cohort Tenon fibroblasts were harvested at the time of ocular surgery, cultured and DNA was extracted. The mitochondrial genome was amplified in two overlapping fragments (9289bp and 7626bp) by long-range PCR and underwent massively parallel sequencing on the Illumina NextSeq 500. Variant annotation and heteroplasmy levels were analysed using the mtDNA-Server (mtdna-server.uibk.ac.at). Known mtDNA, polymorphisms and novel variants were filtered using MITOMAP and control data. 101 POAG patients and 83 disease-negative controls were recruited; Tenon fibroblasts were acquired at the time of ocular surgery from a sub-set of the study group: POAG patients (n=29) and control (n=13). Analysis of mtDNA mutations in the blood demonstrated there were no significant differences (Fisher exact test at p<0.05) in novel or previously disease associated non-synonymous variants in POAG cases versus controls. There was a significant difference in novel mtDNA variants in the POAG Tenon fibroblasts versus control patient fibroblasts (p<0.05). When comparing the paired samples (blood and Tenon fibroblast mtDNA) there were 2 novel potentially-pathogenic variants in the control tissue that were not seen in the control blood or glaucoma blood or Tenon fibroblasts; in the POAG subset there were 11 novel potentially pathogenic, 9 variants of unknown significance and 4 benign novel variants that were not seen in the POAG blood or control blood or Tenon fibroblasts. Only 1 potentially pathogenic variant (m.8801T>C) was found in paired sample (blood/Tenon fibroblast) in one POAG subject. The high frequency of novel mtDNA variation in the Tenon fibroblasts which were absent from blood derived mtDNA in POAG supports the concept that somatic mtDNA mutation occurs in POAG. Mutations are acquired locally in ocular tissue in POAG and are not inherited or germline. Somatic mtDNA mutations in POAG are likely secondary to the local pathophysiological environment and elucidating the mechanism of induced mtDNA damage may offer novel therapeutic opportunities. This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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".