Genome-wide Association Study for Acute Kidney Injury

Pavan K. Bhatraju, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington.
Ian B. Stanaway, Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington.
Melody R. Palmer, Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Rajasree Menon, Michigan Medicine, Ann Arbor, MI, USA.
Jennifer A. Schaub, Michigan Medicine, Ann Arbor, MI, USA.
Steven Menez, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.
Anand Srivastava, Program of Applied Translational Research, Yale School of Medicine, New Haven, CT.
F Perry Wilson, Division of Nephrology and Hypertension, Northwestern University School of Medicine, Chicago, IL, USA.
Krzysztof Kiryluk, Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York City, NY.
Paul M. Palevsky, Kidney Medicine Section, VA Pittsburgh Healthcare System, Pittsburgh, PA and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Abhijit S. Naik, Division of Nephrology, University of Michigan, Ann Arbor, MI.
Sana S. Sakr, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington.
Gail P. Jarvik, Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Chirag R. Parikh, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.
Lorraine B. Ware, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN.
T Alp Ikizler, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN.
Edward D. Siew, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN.
Vernon M. Chinchilli, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA.
Steve G. Coca, Section of Nephrology, Department of Internal Medicine, Mount Sinai School of Medicine, New York, NY.
Amit X. Garg, Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada.
Alan S. Go, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington.
James S. Kaufman, Division of Nephrology, New York University School of Medicine, New York, NY and Division of Nephrology, VA New York Harbor Healthcare System, New York, NY.
Paul L. Kimmel, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, Washington, DC.
Jonathan Himmelfarb, Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington.
Mark M. Wurfel, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington.

Document Type

Journal Article

Publication Date

6-5-2023

Journal

Kidney360

DOI

10.34067/KID.0000000000000175

Abstract

BACKGROUND: While common genetic risks for chronic kidney disease are well established, genetic factors influencing risk for acute kidney injury (AKI) in hospitalized patients are poorly understood. METHODS: We conducted a genome-wide association study in 1,369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) Study; a multi-ethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities and kidney function prior to hospitalization. We then completed functional annotation of top-performing variants for AKI using single cell RNA sequencing data from kidney biopsies in 12 AKI patients and 18 healthy living donors from the Kidney Precision Medicine Project (KPMP). RESULTS: No genome-wide significant associations with AKI risk were found in ASSESS-AKI (p < 5 x 10-8 ). The top two variants with the strongest association with AKI mapped to the dispatched RND transporter family member 1 (DISP1) gene and toll like receptor 5 (TLR5) gene locus, rs17538288 (OR=1.55, 95% CI:1.32-182, p=9.47 x 10-8 ) and rs7546189 (OR=1.53, 95% CI:1.30-1.81, p=4.60 x 10-7 ). In comparison to 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 x 10 -2 ) and thick ascending limb of the loop of Henle (TAL) (adjusted p =8.7 x 10 -3 ) and differential TLR5 gene expression in TAL (adjusted p =4.9 x 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. While 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.

Department

Medicine

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