Genetic Variation and Ultrafiltration with Peritoneal Dialysis
Bibliographic record
Abstract
Key Points There is a large person-to-person variability in ultrafiltration with peritoneal dialysis at the time of starting treatment. In this international cohort study, heritability of peritoneal ultrafiltration with peritoneal dialysis was estimated at 50%. In genome-wide association study, two single-nucleotide variants reached genome-wide significance—rs72631501 in CRK intron with European ancestry and rs1416265, intergenic, with South Asian ancestry. Background There is a large person-to-person variability in ultrafiltration volume with peritoneal dialysis (PD), most of which cannot be accounted for by demographic and clinical differences. In this article, we tested the hypothesis that common genetic variants are associated with peritoneal ultrafiltration and explored one mechanistic pathway identified by genetic studies. Methods We generated estimates of heritability and undertook genome-wide and gene-wise association studies, adjusted for peritoneal solute transfer rate, to test associations of genetic variation with ultrafiltration on peritoneal equilibration test conducted at PD initiation in 2723 participants in the international Biological Determinants of PD (Bio-PD) study. We used a mouse model of PD to study the mechanistic basis for the association of PTGES gene with peritoneal ultrafiltration. Results The peritoneal equilibration test was conducted at a median of 61 (interquartile range, 38–118) days from PD start with a median 4-hour ultrafiltration volume of 250 (interquartile range, 25–465) ml. The heritability of peritoneal ultrafiltration was estimated to be 50% ( P = 0.001). In single-nucleotide variant–wise multiancestry genome-wide association study using TRACTOR software, one single-nucleotide variant reached genome-wide significance in participants with European local ancestry (rs72631501, CRK intron, P = 2.6×10 −8 ) and one in participants with South Asian local ancestry (rs1416265, intergenic, P = 4.2×10 −8 ). Gene-wise analyses showed significant association of 21 genes at false discovery rates (FDRs) <0.10 in the European strata, notably PTGES (FDR=0.053), SLC24A3 (FDR=0.0003), and CRK (FDR=0.04). SLC24A3 remained significant (FDR=0.03) in meta-analysis of the four ancestry strata. Using single-cell RNA sequencing, PTGES localized in peritoneal adipocytes. In a mouse PD model, pharmacologic modulation of prostaglandin E synthase altered dialysate PGE2 levels with changes in adipocyte volume, peritoneal small solute transfer rate, and ultrafiltration volume. Conclusions Common genetic variants accounted for a substantial proportion of the variability in peritoneal ultrafiltration with potential associations with 21 genes, including CRK , PTGES , and SLC24A3 . Functional studies substantiated a potential role for prostaglandin E synthase/prostaglandin E2 in regulating peritoneal ultrafiltration. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT02694068.
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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 | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".