Leveraging AKI Recovery Patterns Reveals a Genome-Wide Significant Variant Associated With a Higher Risk of Non-Resolving AKI
Bibliographic record
Abstract
Background: Genetic studies have focused on associations between genetic variants and the risk for AKI compared to controls, but this framework may be limited because AKI is highly heterogeneous. We hypothesized that a GWAS for distinct AKI recovery patterns (resolving versus non-resolving AKI) would identify novel and robust genetic risks for AKI. Methods: We included 2,271 patients with AKI previously enrolled in three different studies of hospitalized patients (ASSESS-AKI, iSPAAR and HMC Trauma). Resolving AKI was a ≥ 0.3 mg/dL or ≥ 25% decrease in serum creatinine within the first 72 hours after AKI onset (n=1524) and non-resolving AKI was the absence of resolving (n=747). Array-based genome-wide genotypes were obtained from each dataset and imputed with Haplotype Reference Consortium v r1.1. We pooled results from all three studies and used an additive genetic model adjusting for site, age, sex, and the first 10 principal components (significance was p<5x10-8). Results: We identified one variant (rs263152, C>T, frequency 29%) on chromosome 6 that achieved genome-wide significance with the T allele associated with a greater risk of non-resolving AKI (OR=1.47, 95% CI: 1.28-1.68, p=4.28x10-8) (Figure 1). rs263152 is intronic to LOC153910, a long non-coding RNA. In each cohort, the minor allele of rs263152 was consistently associated with a greater risk of non-resolving AKI. Query of the NephQTL database revealed that rs263152 is a cis eQTL for AIG1 (Androgen Induced Gene-1) in tubulointerstitial cells (p=0.007). AIG1 has been implicated in albuminuria in the Framingham Heart Study.Figure 1.: Genome wide significant variant is associated with non-resalving AKI compared to resolving AKI. A. Quantile-quantile plot showing overall adherence to expected p values. The genomic inflation factor based on a median chi-square was estimated at 0.997, indicating negligible variation in population structure between cases and controls. B. Manhattan plot demonstrates rs263152, an intronic SNP in chromosome 6, is significantly associated with a greater risk of non-resolving AKI (OR=1.47, 95% CI: 1.28-1.68, p=4.28x10 -8). C. Forest plot demonstrates a consistent direction of effect with the minor allele of rs263152 associated with a greater risk of non-resolving AKI in all three studies. The size of the boxes represents the sample size of each study.Conclusions: Identification of genetic risks for AKI may be facilitated by a focus on less heterogeneous sub-phenotypes, such as non-resolving AKI. Our findings suggest that genetic variation that alters expression of AIG1 confers greater risk of non-resolving AKI. Funding: NIDDK Support
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 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) | 0.000 | 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".