Leveraging AKI Recovery Patterns Reveals a Genome-Wide Significant Variant Associated With a Higher Risk of Non-Resolving AKI
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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