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. 2023 Jul 1;4(7):870-880.
doi: 10.34067/KID.0000000000000175. Epub 2023 Jun 5.

Genome-wide Association Study for AKI

Pavan K Bhatraju  1   2 , Ian B Stanaway  2 , Melody R Palmer  3 , Rajasree Menon  4 , Jennifer A Schaub  4 , Steven Menez  5 , Anand Srivastava  6 , F Perry Wilson  7 , Krzysztof Kiryluk  8 , Paul M Palevsky  9   10 , Abhijit S Naik  11 , Sana S Sakr  1 , Gail P Jarvik  3 , Chirag R Parikh  5 , Lorraine B Ware  12 , T Alp Ikizler  13 , Edward D Siew  13 , Vernon M Chinchilli  14 , Steve G Coca  15 , Amit X Garg  16 , Alan S Go  17   18   19 , James S Kaufman  20   21 , Paul L Kimmel  22 , Jonathan Himmelfarb  2 , Mark M Wurfel  1   2
Affiliations

Genome-wide Association Study for AKI

Pavan K Bhatraju et al. Kidney360. .

Abstract

Key Points:

  1. Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI.

  2. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI.

Background: Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood.

Methods: We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project.

Results: No genome-wide significant associations with AKI risk were found in Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (P < 5×10−8). The top two variants with the strongest association with AKI mapped to the dispatched resistance-nodulation-division (RND) transporter family member 1 (DISP1) gene and toll-like receptor 5 (TLR5) gene locus, rs17538288 (odds ratio, 1.55; 95% confidence interval, 1.32 to 182; P = 9.47×10−8) and rs7546189 (odds ratio, 1.53; 95% confidence interval, 1.30 to 1.81; P = 4.60×10−7). In comparison with kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential DISP1 expression in proximal tubular epithelial cells (adjusted P = 3.9×10−2) and thick ascending limb of the loop of Henle (adjusted P = 8.7×10−3) and differential TLR5 gene expression in thick ascending limb of the loop of Henle (adjusted P = 4.9×10−30).

Conclusions: AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies, and pathophysiology that may limit the identification of genetic variants. Although no variants reached genome-wide significance, we report two variants in the intergenic region between DISP1 and TLR5, suggesting this region as a novel risk for AKI susceptibility.

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Conflict of interest statement

P.K. Bhatraju reports the following: Research Funding: Roche Diagnostics. V.M. Chinchilli reports the following: Advisory or Leadership Role: Allergan; Astra-Zeneca; Biohaven; Jannsen; Regeneron; Sanofi. S.G. Coca reports the following: Consultancy: 3ive, Axon, Bayer, Boehringer Ingelheim, Nuwellis, Renalytix, Reprieve Cardiovascular, Takeda, Vifor; Ownership Interest: pulseData, Renalytix; Research Funding: ProKidney, Renal Research Institute, Renalytix, XORTX; Patents or Royalties: Renalytix; and Other Interests or Relationships: Associate Editor for Kidney360, Editorial Boards of JASN, CJASN, Kidney International. A.X. Garg reports the following: Research Funding: Astellas, Baxter; Advisory or Leadership Role: Currently on the Editorial Boards of Kidney Int and AJKD; and Other Interests or Relationships: Served as the Medical Lead Role to Improve Access to Kidney Transplantation and Living Kidney Donation for the Ontario Renal Network (government funded agency located within Ontario Health). This position ended October 2022. A.S. Go reports the following: Research Funding: Amarin Pharmaceuticals, Bristol MeyersSquibb, CSL Behring, Janssen Research and Development, Novartis, Pfizer. J. Himmelfarb reports the following: Consultancy: Maze Therapeutics; Ownership Interest: Kuleana Technology, Inc.; Research Funding: Aurinia Pharmaceuticals; Honoraria: various academic institutions for invited lectures; Patents or Royalties: Patents held and patents pending owned by the University of Washington; Advisory or Leadership Role: CJASN (Ed board); BMC Medicine (Ed. Board), Nature Reviews Nephrology (Advisory Board); and Other Interests or Relationships: Research grant support from Northwest Kidney Centers; Founder, CEO, President and equity holder, Kuleana Technology, Inc. T.A. Ikizler reports the following: Consultancy: Fresenius-Kabi, Nestle; Research Funding: NIDDK; Veterans Affairs; Honoraria: Fresenius-Kabi, Nestle; and Advisory or Leadership Role: Kidney International. G.P. Jarvik reports the following: Ownership Interest: literally hundreds managed by a professional manager and not chosen by me or my spouse; and Advisory or Leadership Role: I was the 2022 Past President of the American Society of Human Genetics. J.S. Kaufman reports the following: Consultancy: National Kidney Foundation; Otsuka Pharmaceutical; Ownership Interest: Amgen; Advisory or Leadership Role: Digestive and Kidney Diseases, National Institute of Diabetes, paid Steering Committee Chair; and Other Interests or Relationships: Associate Editor, American Journal of Kidney Disease. P.L. Kimmel reports the following: Employer: National Institute of Diabetes and Digestive Kidney Diseases (NIDDK); Ownership Interest: As a Federal Employee at NIDDK, my holdings are reviewed each year for potential conflict of interest. At this time my only stock holding related in any fashion to health care is CVS; Patents or Royalties: Elsevier: Royalties for co-editing Chronic Renal Disease and Psychosocial Aspects of Chronic Kidney Disease; Advisory or Leadership Role: Unpaid member of Board of Directors of Academy of Medicine of Washington, DC; and Other Interests or Relationships: Co-Editor, Chronic Renal Disease Academic Press; Co-Editor, Psychosocial Aspects of Chronic Kidney Disease. Academic Press; Royalties. K. Kiryluk reports the following: Consultancy: Calvariate, HiBio; and Research Funding: Aevi Genomics, AstraZeneca, Bioporto, Vanda, Visterra. S. Menez reports the following: Research Funding: RenalytixAI. A.S. Naik reports the following: Consultancy: CareDX—External Advisor; and Honoraria: CareDx. P.M. Palevsky reports the following: Consultancy: Janssen Research & Development, LLC; and Advisory or Leadership Role: National Kidney Foundation: Past President, Member, Scientific Advisory Board; Renal Physicians Association: Member, Quality, Safety and Accountability Committee; Quality Insights Renal Network 4: Chair, Medical Review Board; UpToDate: Section Editor, RAcute Kidney Injury; Journal of Intensive Care Medicine: Member, Editorial Board. M.R. Palmer reports the following: Employer: Natera, Inc.; and Ownership Interest: Natera, Inc. C.R. Parikh reports the following: Consultancy: Genfit Biopharmaceutical Company; Ownership Interest: Renaltix AI Research Funding: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Heart, Lung and Blood Institute (NHLBI); and Advisory or Leadership Role: Genfit Biopharmaceutical Company; Renalytix. J.A. Schaub reports the following: Consultancy: Cook Biotech (Spouse); Nuvira (Spouse); Uptodate (Spouse). E.D. Siew reports the following: Ownership Interest: Amazon stock, Apple stock; Patents or Royalties: Author for UptoDate (royalties) and Advisory or Leadership Role: Editorial board of CJASN. A. Srivastava reports the following: Consultancy: CVS Caremark; Tate & Latham (Medicolegal consulting); and Honoraria: AstraZeneca; Bayer; FNIH; Horizon Therapeutics PLC. I.B. Stanaway reports the following: Ownership Interest: I have an LLC, Byrell Systems, registered in Washington State that is solely owned by me, Dr. Ian Byrell Stanaway.; and Other Interests or Relationships: ASN Member. F.P. Wilson reports the following: Consultancy: Translational Catalyst, LLC; Ownership Interest: Owner of Efference, LLC; Research Funding: Amgen; Boeringher-Ingelheim; Vifor, Whoop; Advisory or Leadership Role: Editorial Board—American Journal of Kidney Disease; Editorial Board—Clinical Journal of the American Society of Nephrology; and Other Interests or Relationships: Medical columnist-Medscape. L.B. Ware reports the following: Consultancy: Akebia, Global Blood Therapeutics, Santhera; Ownership Interest: Virtuoso Surgical; and Research Funding: Boehringer Ingelheim; Genentech. M.M. Wurfel reports the following: Consultancy: Roche Diagnostics; and Research Funding: Roche. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Patient flow. One thousand three hundred and sixty-nine participants were included in ASSESS-AKI genetic cohort with 637 AKI cases and 732 non-AKI controls. ASSESS-AKI, Assessment, Serial Evaluation, and Subsequent Sequelae of AKI.
Figure 2
Figure 2
Manhattan plots generated from genome-wide association study analysis of the AKI cases and controls. Plots include (A) association results for imputed single-nucleotide polymorphisms (variants) with AKI in the discovery cohort. (B) Genomic locus for the DISP1-TLR5 top hits, rs17538288 and rs7546189 at higher magnification. LD, r2, is indicated relative to the variant with lowest P value (purple marker) by colored scale. Notice that the top two DISP1-TLR5 hits are not in LD with each other (r2=0.24). Genes located near each locus are displayed in the bottom panels. DISP1, dispatched resistance-nodulation-division (RND) transporter family member 1; LD, linkage disequilibrium; TLR5, toll-like receptor 5.
Figure 3
Figure 3
Single-cell RNA sequencing in living donor (LD) (n=18) and AKI (n=12) kidney biopsy specimens demonstrates DISP1 and TLR5 gene expression in multiple cell lines. DISP1 gene expression is significantly upregulated in PT (adjusted P = 3.9×10−2) and TAL cell types (adjusted P = 8.7×10−3) in AKI compared with no AKI, while TLR5 expression is downregulated in TAL cell types (adjusted P = 4.9×10−30) in AKI compared with no AKI. ATL, ascending thin limb of the loop of Henle; CNT, connecting tubule; DCT, distal convoluted tubule; DISP1, dispatched RND transporter family member 1; DTL, descending thin limb of the loop of Henle; EC, endothelial cells; IC, intercalated cells; PC, principal cells; POD, podocytes; PT, proximal tubular epithelial cells and 1–3 segments; TAL, thick ascending limb of the loop of Henle; TLR5, toll-like receptor 5.
See this image and copyright information in PMC

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