Abstract
Background and AimThe nuclear farnesoid X receptor (FXR) regulates critical pathways of hepatic metabolism, inflammation, and gut mucosal barrier. Thus, we investigated the association of FXR‐single nucleotide polymorphism (SNPs) with hepatic decompensation and liver‐related mortality in patients with advanced chronic liver disease.MethodsTwo FXR‐SNPs (rs56163822 G > T and rs35724 G > C) were genotyped in a cohort of 402 prospectively characterized patients with hepatic venous pressure gradient (HVPG) ≥ 6 mmHg.ResultsOnly 19 patients (4.7%) harbored a rs56163822 T‐allele and had less pronounced liver disease as indicated by lower Child–Pugh score (CPS, 6 ± 1 vs 7 ± 2 points, P = 0.034) and higher albumin levels (38.9 ± 4.9 vs 35.9 ± 5.9 g/L, P = 0.026). In contrast, n = 267 (66.4%) patients harbored minor rs35724 allele (G/C or C/C) and had more advanced liver disease, as indicated by a higher model of end‐stage liver disease (11 ± 4 vs 10 ± 3, P = 0.016), while other baseline characteristics were similar across FXR‐SNP genotypes. In compensated CPS‐A patients, the rs35724 minor allele was independently protective for the development of ascites (adjusted hazard ratio [aHR] = 0.411, 95% confidence interval (95% CI): 0.191–0.885; P = 0.023) and tended to reduce the risk of hepatic decompensation (aHR = 0.625, 95% CI: 0.374–1.044, P = 0.072) in multivariate analyses. Of note, transplant‐free survival was longer in patients with rs35724 minor allele and HVPG ≥ 10 mmHg (at 5 years: 68.2% vs 55.8%, P = 0.047) and those with HVPG ≥ 16 mmHg (63.3% vs 44.0%, P = 0.021). After adjusting for established risk factors, the rs35724 minor allele was independently associated with reduced liver‐related mortality in the overall cohort (aHR = 0.658, 95% CI: 0.434–0.998, P = 0.049), in compensated CPS‐A patients (aHR = 0.488, 95% CI: 0.252–0.946, P = 0.034), in patients with HVPG ≥ 10 mmHg (aHR = 0.547, 95% CI: 0.346–0.864, P = 0.010), and in patients with HVPG ≥ 16 mmHg (aHR = 0.519, 95% CI: 0.307–0.878, P = 0.014).ConclusionThe FXR‐SNP rs35724 was associated with a reduced risk for development of ascites and liver‐related mortality in patients with advanced chronic liver disease.
Highlights
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and main nuclear bile acid receptor that regulates the expression of key target genes in bile acid, lipid, and glucose metabolism.[1–3] The receptor is highly expressed in the liver and ileum and is involved in metabolic pathways and in hepatic inflammation and fibrosis.[4,5] FXR agonists have been shown to reduce liver fibrosis, vascular remodeling, and sinusoidal dysfunction, as well as portal hypertension in experimental studies.[6,7]Chronic liver disease progresses from fibrosis to cirrhosis, which leads to portal hypertension
For a better understanding of modulators of liver disease progression, genetic factors have been increasingly investigated: For example, the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (C > G) single nucleotide polymorphism (SNP) has been associated with an increased risk for hepatic decompensation and liver-related mortality.[12,22]
P values
Summary
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and main nuclear bile acid receptor that regulates the expression of key target genes in bile acid, lipid, and glucose metabolism.[1–3] The receptor is highly expressed in the liver and ileum and is involved in metabolic pathways and in hepatic inflammation and fibrosis.[4,5] FXR agonists have been shown to reduce liver fibrosis, vascular remodeling, and sinusoidal dysfunction, as well as portal hypertension in experimental studies.[6,7]Chronic liver disease progresses from fibrosis to cirrhosis, which leads to portal hypertension. We investigated the association of FXR-single nucleotide polymorphism (SNPs) with hepatic decompensation and liver-related mortality in patients with advanced chronic liver disease. After adjusting for established risk factors, the rs35724 minor allele was independently associated with reduced liver-related mortality in the overall cohort (aHR = 0.658, 95% CI: 0.434–0.998, P = 0.049), in compensated CPS-A patients (aHR = 0.488, 95% CI: 0.252–0.946, P = 0.034), in patients with HVPG ≥ 10 mmHg (aHR = 0.547, 95% CI: 0.346–0.864, P = 0.010), and in patients with HVPG ≥ 16 mmHg (aHR = 0.519, 95% CI: 0.307–0.878, P = 0.014). Conclusion: The FXR-SNP rs35724 was associated with a reduced risk for development of ascites and liver-related mortality in patients with advanced chronic liver disease
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