Farnesoid-X Receptor single nucleotide polymorphism rs35724 is potentially associated with patients’ outcome in decompensated liver cirrhosis

Mueller, Niklas; Fischer, Josiane; Krohn, Sandra; Böhlig, Albrecht; Herta, Toni; Domeratius, C.; Herber, Adam; Berg, Tore Julsrud; Engelmann, Cornelius

doi:10.1016/s0168-8278(17)31537-4

Cited by 3 publications

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“…Indeed, FXR activity can be modulated by variants of the Nuclear Receptor Subfamily 1 Group H Member 4 ( NR1H4) gene encoding for FXR. Consistently, a preliminary report on a cohort of cirrhotic patients suggested that the NR1H4 rs35724 G>C intronic variant was associated with better liver function and improved transplant‐free survival after 180 days of follow‐up in a cohort of cirrhotic patients 17 . Along this line, a study in patients with advanced chronic liver disease related to different aetiologies reported that the NR1H4 rs35724 G>C was independently associated with a reduced risk for the development of ascites and liver‐related mortality 18 …”

Section: Introductionmentioning

confidence: 80%

“…Consistently, a preliminary report on a cohort of cirrhotic patients suggested that the NR1H4 rs35724 G>C intronic variant was associated with better liver function and improved transplant-free survival after 180 days of follow-up in a cohort of cirrhotic patients. 17 Along this line, a study in patients with advanced chronic liver disease related to different aetiologies reported that the NR1H4 rs35724 G>C was independently associated with a reduced risk for the development of ascites and liver-related mortality. 18 In this study, in a large multicentre cohort of patients who underwent liver biopsy for suspected steatohepatitis, we tested the impact of the NR1H4 rs35724 G>C variant on liver damage.…”

Section: Introductionmentioning

confidence: 99%

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NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Grimaudo

Dongiovanni

Pihlajamäki

et al. 2021

Liver International

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Background and Aims Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). Results The NR1H4 rs35724 CC genotype, after adjusting for clinic‐metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62‐0.95; P = .01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47‐0.83; P = .001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67‐0.98; P = .04). The C allele was associated with higher total circulating cholesterol (P = .01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. Conclusions Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR‐targeted therapy warrants further investigation.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Grimaudo

Dongiovanni

Pihlajamäki

et al. 2021

Liver International

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Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension

Semmler

Simbrunner

Scheiner

et al. 2019

J of Gastro and Hepatol

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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.

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<i>NR1H4</i> rs35724 G>C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease

et al. 2020

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Farnesoid-X Receptor single nucleotide polymorphism rs35724 is potentially associated with patients’ outcome in decompensated liver cirrhosis

Cited by 3 publications

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NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension

<i>NR1H4</i> rs35724 G>C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease

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Farnesoid-X Receptor single nucleotide polymorphism rs35724 is potentially associated with patients’ outcome in decompensated liver cirrhosis

Cited by 3 publications

References 0 publications

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension

<i>NR1H4</i> rs35724 G&gt;C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease

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<i>NR1H4</i> rs35724 G>C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease