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