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Abstract: FR-PO094

Genome-Wide Association Study (GWAS) in Critically Ill Sepsis Patients Identifies Single Nucleotide Polymorphisms (SNPs) Associated with AKI by Multiple Definitions

Session Information

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

  • Miano, Todd A., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Shashaty, Michael G. S., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Reilly, John P., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Jones, Tiffanie, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Feng, Rui, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Turner, Alexandra Paige, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Dunn, Thomas, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Ittner, Caroline, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Anderson, Brian J., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Christie, Jason, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Giannini, Heather, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Meyer, Nuala J., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background

Identifying replicable genetic variants associated with AKI has been challenging, potentially related to differences in AKI definition across studies. We conducted GWAS of AKI, defined multiple ways, in critically ill sepsis patients.

Methods

We included 1955 critically ill patients without ESKD enrolled in a sepsis cohort from 2011-2020. We extracted genomic DNA from whole blood and genotyped with the Affymetrix Axiom TxArray. We defined AKI using 1) Kidney Disease Improving Global Outcomes (KDIGO) creatinine (Cr) criteria which include both worsening and rapidly resolving AKI, and 2) Acute Kidney Injury Network (AKIN) Cr criteria which require Cr increase from admission. We used PLINK to conduct additive multivariable logistic regression, adjusting for age, sex, and principal components, stratified by European (n=1312) or African (n=643) ancestry (EA, AA). We assessed SNPs associated with AKI at p<5x10-5 by one definition for significance at p<5x10-3 by the other.

Results

AKIN-AKI occured in 43% of EA patients and 45% of AA patients, while KDIGO-AKI occured in 58% of EA patients and 63% of AA patients. In AAs, 21 had p<5x10-5 for AKIN-AKI and 18 for KDIGO-AKI; 4 SNPs were associated with the other AKI definition at p<5x10-3 (Table). NOD1 encodes a bacterial pattern-recognition receptor that initiates inflammation. ERO1B encodes an oxidoreductase in the endoplasmic reticulum that regulates reactive oxygen species production. In EAs, 14 SNPs had p<5x10-5 for AKIN-AKI and 11 for KDIGO-AKI; none were associated with the other AKI definition at p<5x10-3. However, NKAIN2 is extensively expressed in the kidney and is associated with glomerular filtration rate in children, while rs10031539 (KCNIP) is associated with CKD.

Conclusion

We identified SNPs associated with both KDIGO and AKIN defined AKI that may be pathophysiologically relevant.

SNPs of interest
SNPFunctionGeneAncestryAKIN OR (95%CI)pKDIGO OR (95%CI)p
rs1104940IntronicNKAIN2EA0.71 (0.61-0.83)2.02 x 10-50.81 (0.70-0.95)7.68 x 10-3
rs10031539IntronicKCNIPEA1.42 (1.21-1.67)2.01 x 10-51.25 (1.07-1.47)6.52 x 10-3
rs113286694IntronicNOD1AA0.54 (0.38-0.75)2.58 x 10-40.51 (0.37-0.71)4.72 x 10-5
rs1749557IntronicERO1BAA1.64 (1.31-2.10)1.99 x 10-51.46 (1.16-1.84)1.44 x 10-3
rs2463188IntronicERO1BAA1.63 (1.29-2.04)2.59 x 10-51.39 (1.11-1.75)4.73 x 10-3

Funding

  • NIDDK Support