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Abstract: TH-OR02

Leveraging AKI Recovery Patterns Reveals a Genome-Wide Significant Variant Associated With a Higher Risk of Non-Resolving AKI

Session Information

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology‚ Risk Factors‚ and Prevention

Authors

  • Bhatraju, Pavan K., University of Washington, Seattle, Washington, United States
  • Stanaway, Ian Byrell, University of Washington, Seattle, Washington, United States
  • Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
  • Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Ikizler, Talat Alp, Vanderbilt University, Nashville, Tennessee, United States
  • Siew, Edward D., Vanderbilt University, Nashville, Tennessee, United States
  • Chinchilli, Vernon M., The Pennsylvania State University, University Park, Pennsylvania, United States
  • Garg, Amit X., Western University, London, Ontario, Canada
  • Coca, Steven G., Mount Sinai Health System, New York, New York, United States
  • Go, Alan S., University of California San Francisco, San Francisco, California, United States
  • Kaufman, James S., New York University, New York, New York, United States
  • Kimmel, Paul L., The George Washington University, Washington, District of Columbia, United States
  • Parikh, Chirag R., Johns Hopkins University, Baltimore, Maryland, United States
  • Wurfel, Mark M., University of Washington, Seattle, Washington, United States
  • Himmelfarb, Jonathan, University of Washington, Seattle, Washington, United States
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.

Conclusion

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