Impact of farnesoid X receptor (FXR) polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension

Background and Aims:

The nuclear farnesoid X receptor (FXR) regulates critical pathways of hepatic metabolism, inflammation, and gut integrity. However, the impact of FXR single nucleotide polymorphisms (SNPs) on portal hypertension-induced complications remains unknown. Thus, we investigated the association of FXR-SNPs with hepatic decompensation and liver-related transplant-free mortality in patients with advanced chronic liver disease (ACLD).

Methods:

Two FXR-SNPs (rs56163822 G>T, rs35724 G>C) were genotyped in a cohort of 402 prospectively characterized patients with hepatic venous pressure gradient (HVPG) ≥6 mmHg.

Results:

Only 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 at least one minor rs35724 allele (G/C or C/C) and had more pronounced liver disease, as indicated by a higher MELD score (11 ± 4 vs. 10 ± 3points; p = 0.016). Other baseline characteristics including the etiology of liver disease and HVPG were comparable between 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 any hepatic decompensation (aHR: 0.625, 95%CI: 0.374 – 1.044; p = 0.072) in multivariate analyses. CPS-A patients with rs35724 minor allele had numerically longer transplant-free survival (at 5 years: 82% vs. 69%; p = 0.112). After adjusting for established risk factors, harboring the rs35724 minor allele was independently associated with reduced liver-related transplant-free mortality in compensated CPS-A patients (aHR: 0.488, 95%CI: 0.252 – 0.946, p = 0.034) but also in the overall cohort (aHR: 0.658, 95%CI: 0.434 – 0.998; p = 0.049).

Tab. 1:

Transplant-free mortality

	A Overall cohort, n = 402			B CPS-A patients, n = 221
	aHR	95%CI	HR	aHR	95%CI	p-value
Age, per 10 years	1.381	1.134 – 1.681	0.001	1.224	0.882 – 1.698	0.227
Male gender (vs. female)	1.954	1.165 – 3.277	0.011	1.978	0.866 – 4.515	0.106
HVPG, per mmHg	1.020	0.985 – 1.056	0.257	1.067	0.999 – 1.140	0.054
MELD, per point	0.974	0.910 – 1.042	0.439	0.851	0.712 – 1.016	0.074
Albumin, per g/dL	0.904	0.871 – 0.940	< 0.001	0.932	0.853 – 1.018	0.119
rs56163822 SNP (G/T vs. wild-type)	1.027	0.370 – 2.855	0.959	0.924	0.215 – 3.970	0.915
rs35724 SNP (G/C or C/C vs. wild-type)	0.658	0.434 – 0.998	0.049	0.488	0.252 – 0.946	0.034

Conclusion:

The rs35724 C-allele was associated with a reduced risk for ascites development as well as liver-related transplant-free mortality in patients with ACLD. Further studies are needed to investigate the underlying mechanisms and to confirm the prognostic value of the rs35724 genotype for hepatic decompensation and mortality.