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

Abstract

Background and Aims: Tolvaptan, an orally active vasopressin V2-receptor antagonist, has been used for patients with di cult-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 e cacy 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 signi cant 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 signi cantly associated with the response (OR = 1.03, p = 0.02 and OR = 4.24, p < 0.0001, 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 nonresponders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, speci city was 70% and AUC was 0.774. Conclusion: SVEP1 rs2991364 was identi ed as the speci c SNP for the tolvaptan response. The prediction score can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Management of cirrhotic ascites: Seven‐step treatment protocol based on the Japanese evidence‐based clinical practice guidelines for liver cirrhosis 2020

“…Factors identified included baseline body weight and blood urea nitrogen levels in a post hoc analysis of the Japanese tolvaptan phase 2/3 trials, 39 and blood urea nitrogen levels, serum sodium levels, and the presence of a single nucleotide polymorphism (rs2991364) of the SVEP1 gene in a genome-wide association study in 550 Japanese patients. 40 In line with Japanese guidelines, 11,12 tolvaptan nonresponders should receive intravenous spironolactone and intravenous furosemide 20 mg, plus albumin (Figure 4). Individuals without renal dysfunction should be given intravenous potassium canrenoate 100-200 mg with intravenous furosemide 20 mg, plus albumin (Figure 3).…”

“…Given the potential for improvement in prognosis, studies have investigated factors predictive of tolvaptan efficacy. Factors identified included baseline body weight and blood urea nitrogen levels in a post hoc analysis of the Japanese tolvaptan phase 2/3 trials, 39 and blood urea nitrogen levels, serum sodium levels, and the presence of a single nucleotide polymorphism (rs2991364) of the SVEP1 gene in a genome‐wide association study in 550 Japanese patients 40 …”

Algorithm of ascites management for liver cirrhosis in the tolvaptan era: Paradigm shift treatment improves the outcomes of cirrhotic patients?

“…4 As a genetic factor, the SVEP1 rs2991364 single nucleotide polymorphism has been reported to be associated with the tolvaptan response. 13 Tolvaptan increases the serum level of albumin, decreases the ammonia level, and preserves renal function after 1 year of treatment. 14 Furthermore, it is expected to improve QOL and the survival rate of cirrhosis.…”

“…Therefore, tolvaptan has been presumed to be more effective for cases of early stage ascites and early initiation of tolvaptan is recommended when conventional diuretics are ineffective 4 . As a genetic factor, the SVEP1 rs2991364 single nucleotide polymorphism has been reported to be associated with the tolvaptan response 13 …”

Endotoxin Activity Reflects an Increase in Body Temperature in Cirrhotic Patients With Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy

“…Refractory ascites, one of the most serious complications in patients with cirrhosis and ascites, has a prevalence of 5-10% in 5 years (1) and a post diagnosis survival rate of 50% at 6-12 months (2,3). Most patients with decompensated cirrhosis who develop large volumes of ascitic fluid notice abdominal distention, which may markedly impair the patients' quality of life (4). Evidencebased clinical practice guidelines for liver cirrhosis have shown that diuretic resistance or poor diuretic response is an indication for large abdominal paracentesis or cell-free and concentrated ascites reinfusion therapy (CART) (5,6), with fever, high blood pressure, headache, and shaking with chills having been reported as CART-related adverse events (7).…”