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

Hideto Kawaratani, Hiromi Sawai, Masaya Onishi, Tomomi Kogiso, Noritomo Shimada, Haruki Uojima, Tomoaki Nakajima, Naoki Matsumoto, Kenichi Ikejima, Toru Ishikawa, Shuji Terai, Hiroyuki Motoyama, Atsumasa Komori, Noboru Hirashima, Satoru Saito, Yuichiro Eguchi, Masanori Nojima, Yosuke Kawai, Masakuni Tateyama, Hitoshi YoshijiYasuhito Tanaka

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Background & Aims: Tolvaptan, 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: Genome-wide association study 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 × 10-8). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P =.003; OR = 1.02, P =.02 and OR = 3.98, P =.000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. Conclusion: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Original languageEnglish
Pages (from-to)2944-2953
Number of pages10
JournalLiver International
Issue number12
Publication statusPublished - Dec 2021


  • Polydom
  • blood urine nitrogen (BUN)
  • genome-wide association study (GWAS)
  • hepatic ascites
  • liver cirrhosis
  • non-responder


Dive into the research topics of 'A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites'. Together they form a unique fingerprint.

Cite this