Transcriptomic Assessment of GRP78 as a Mediator of CKD
Bibliographic record
Abstract
Background: Protein misfolding causes endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). The 78-kDa glucose-regulated protein (GRP78) is an ER stress-induced chaperone protein and regulator of UPR. GRP78 overexpression protects rat ventricular cardiomyocytes from ischemia-reperfusion injury and regulates the profibrotic response to high glucose in glomerular mesangial cells. Homozygous knockout of GRP78 is lethal in mice. We hypothesized that genetically altered GRP78 expression or rare variants in GRP78 would be associated with chronic kidney disease (CKD). Methods: We assessed genetic variants' impact on GRP78 gene expression in the expression quantitative trait loci genetics consortium (n=31,684). We used a two-sample Mendelian Randomization analysis to assess the effect of genetically predicted GRP78 expression on CKD (n=480,698), cross-sectional eGFR (n=1,508,659), eGFR decline (n=343,339), and urinary albumin-to-creatinine ratio (uACR; n=348,964) using European ancestry summary-level genome-wide association studies (GWAS). The prevalence of GRP78 missense and loss-of-function variants was assessed in gnomAD, BRAVO, and in 157,528 UK Biobank participants. We performed linear regression to test for association between GRP78 rare variant carrier status and kidney phenotypes adjusted for age, sex, and ancestry. Results: The latest GWAS reports association of variants near GRP78 and eGFR (lowest P=8.9e-09). A 13-variant Mendelian randomization instrument explained 2.8% of variability in GRP78 expression, but was not associated with cross-sectional eGFR, eGFR decline, CKD, or uACR (P>0.05). GRP78 is relatively intolerant of genetic variability, with a loss-of-function upper bound fraction of 0.41 and missense observed/expected ratio of 0.41. Presence of rare-variants was marginally associated with a 6.4% increase in uACR (P=0.01), a 1.5% decline in eGFRCys (P=0.02), but not significantly associated with cross-sectional eGFR (β=-0.004,P=0.5) or CKD (OR=1.31,95% CI:1-1.73,P=0.05). Conclusions: GRP78 is relatively intolerant of genetic variation consistent with selection against heterozygous variation. Nevertheless, GWAS and rare variant analysis show a nominal association of variants around GRP78 with kidney phenotypes. In contrast, genetically-predicted variation in GRP78 expression was not associated with kidney phenotypes.
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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 | 0.000 | 0.000 |
| 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".