A genome‐wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites

Background and Aims: Tolvaptan, an orally active vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan’s efficacy for patients with hepatic ascites. Methods: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; > 1.5 kg decrease of BW) were included in the GWAS and replication study. Results: GWAS showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 x 10− 8). Univariate and multivariate analyses showed that blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 1.03, p = 0.02 and OR = 4.24, p SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.