Abstract
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. 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; >1.5kg decrease of BW) were included in the GWAS and replication study. 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. 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.
Highlights
Hepatic ascites, the accumulation of fluid in the abdominal cavity due to liver disease, is a difficult condition to treat
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 odds ratio (OR) = 4.24, p < 0.0001, respectively)
SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response
Summary
The accumulation of fluid in the abdominal cavity due to liver disease, is a difficult condition to treat. In European guidelines, high-dose diuretics (160mg furosemide, spironolactone 400mg) are used for uncontrolled hepatic ascites [1]. Japanese patients are usually intolerant to high-dose conventional diuretics (furosemide and spironolactone) because of dehydration or hyponatremia. Since December 2013, tolvaptan, an orally active vasopressin V2-receptor antagonist, has been used in Japan for patients with ascites that are difficult to treat with conventional diuretics [2]. When ascites is uncontrolled by conventional diuretics, tolvaptan is administered at a dose of 3.75 or 7.5mg. In a Japanese multicenter retrospective study, responders to tolvaptan were defined as patients who had body weight (BW) loss of 1.5 kg/week which reflect the improvement of ascites volume and symptoms [7]. An orally active vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. 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
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