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Abstract: FR-OR022

Plasma Angiopoietin-2 Concentrations Mediate the Contribution of Genetic Variation in the Angiopoietin-2 Gene to Development of AKI Sub-Phenotypes

Session Information

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

  • Bhatraju, Pavan K., University of Washington, Seattle, Washington, United States
  • Himmelfarb, Jonathan, Kidney Research Institute, Seattle, Washington, United States
  • Wurfel, Mark M., University of Washington, Seattle, Washington, United States
Background

Plasma angiopoietins 1 (Ang-1) and 2 (Ang-2), markers of endothelial stability and dysfunction, have been implicated in the development of acute kidney injury (AKI). Using latent class analysis, we previously identified two AKI sub-phenotypes (AKI-SP1 and AKI-SP2). Critically ill subjects classified as AKI-SP2 had worse clinical outcomes and higher markers of endothelial dsyfuntion (high Ang-2 and low Ang-1) compared to AKI-SP1 (low Ang-2 and high Ang-1). It is unknown whether Ang-1 and 2 are markers of disease or act as a causal mediator in the development of AKI sub-phenotypes.

Methods

A targeted genetic study was performed to identify SNPs within 50 kb of the Angiopoietin 1 (ANGPT1) and Angiopoietin 2 (ANGPT2) genes associated with AKI- SP2 in 452 AKI subjects from the iSPAAR cohort. Association testing was performed on 190 SNPs. Causal inference analysis was used to determine the role of genetic variation and circulating angiopioetins in the development of AKI-SP2.

Results

An intronic SNP, rs2920656, near the ANGPT2 gene (≈ 30kb downstream to the 3’ position) was associated with reduced risk of AKI-SP2 (Bonferroni, p=0.003) and decreased Ang-2 concentrations (p=0.002) adjusting for age, gender, sepsis and 5 principal components of ancestry. Causal inference analysis indicated that the total effect of the SNP (rs2920656) on AKI-SP2 was Beta = -0.16 (95% CI -0.23 to -0.09, p=1.0 x 10-4) and the indirect effect was Beta = -0.07 (95% CI -0.11, -0.03, p=0.001). This suggests that for each minor allele (T allele) of the genetic variant the risk of developing AKI-SP2 decreases by 16%. When comparing the total effect to the indirect effect through a mediation analysis, 42% of the SNP’s prognostic effect was mediated through Ang-2 plasma concentrations (Figure 1).

Conclusion

Our findings support the importance of ANGPT2 in AKI pathophysiology by mediating plasma Ang-2 levels.

Funding

  • NIDDK Support