Genome-wide Association Study for Acute Kidney Injury
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.
Bhatraju, Pavan K.; Stanaway, Ian B.; Palmer, Melody R.; Menon, Rajasree; Schaub, Jennifer A.; Menez, Steven; Srivastava, Anand; Wilson, F Perry; Kiryluk, Krzysztof; Palevsky, Paul M.; Naik, Abhijit S.; Sakr, Sana S.; Jarvik, Gail P.; Parikh, Chirag R.; Ware, Lorraine B.; Ikizler, T Alp; Siew, Edward D.; Chinchilli, Vernon M.; Coca, Steve G.; Garg, Amit X.; Go, Alan S.; Kaufman, James S.; Kimmel, Paul L.; Himmelfarb, Jonathan; and Wurfel, Mark M., "Genome-wide Association Study for Acute Kidney Injury" (2023). GW Authored Works. Paper 2761.